Annotations: 7DL2

Domain Annotation: ECOD Classification ECOD Database Homepage

Chains	Family Name	Domain Identifier	Architecture	Possible Homology	Homology	Topology	Family	Provenance Source (Version)
E	F_UNCLASSIFIED	e7dl2E2	A: alpha arrays	X: Ypt/Rab-GAP domain of gyp1p-like	H: Ypt/Rab-GAP domain of gyp1p (From Topology)	T: Ypt/Rab-GAP domain of gyp1p	F: F_UNCLASSIFIED	ECOD (1.6)
E	PF00566	e7dl2E1	A: alpha arrays	X: Ypt/Rab-GAP domain of gyp1p-like	H: Ypt/Rab-GAP domain of gyp1p (From Topology)	T: Ypt/Rab-GAP domain of gyp1p	F: PF00566	ECOD (1.6)

Protein Family Annotation Pfam Database Homepage

Chains	Accession	Name	Description	Comments	Source
B [auth A], C [auth B]	PF03542	Tuberin (Tuberin)	Tuberin	-	Family
B [auth A], C [auth B]	PF02145	Rap/ran-GAP (Rap_GAP)	Rap/ran-GAP	-	Family
B [auth A], C [auth B]	PF11864	Domain of unknown function (DUF3384) (DUF3384)	Domain of unknown function (DUF3384)	-	Family
E	PF00566	Rab-GTPase-TBC domain (RabGAP-TBC)	Rab-GTPase-TBC domain	-	Family

Gene Ontology: Gene Product Annotation Gene Ontology Database Homepage

Chains	Polymer	Molecular Function	Biological Process	Cellular Component
A [auth D], D [auth C]	Hamartin	molecular function inhibitor activity molecular function regulator activity ATPase inhibitor activity ATPase regulator activity protein binding binding protein-folding chaperone binding Hsp90 protein binding heat shock protein binding Hsp70 protein binding	regulation of protein stability biological regulation regulation of biological quality protein stabilization response to stimulus immune response immune system process adaptive immune response cell population proliferation cellular process developmental process heart development multicellular organismal process cellular developmental process regulation of protein stability biological regulation regulation of biological quality protein stabilization response to stimulus immune response immune system process adaptive immune response cell population proliferation cellular process developmental process heart development multicellular organismal process cellular developmental process cardiac muscle tissue development cardiac muscle cell differentiation animal organ development muscle cell differentiation tissue development cardiocyte differentiation striated muscle tissue development circulatory system development muscle structure development multicellular organism development cell differentiation anatomical structure development striated muscle cell differentiation muscle tissue development system development negative regulation of ATP-dependent activity regulation of ATP-dependent activity regulation of molecular function negative regulation of molecular function regulation of cellular process cellular biosynthetic process organonitrogen compound biosynthetic process regulation of primary metabolic process post-transcriptional regulation of gene expression organic substance metabolic process organic substance biosynthetic process protein metabolic process regulation of biosynthetic process regulation of biological process organonitrogen compound metabolic process cellular metabolic process regulation of protein metabolic process regulation of cellular metabolic process primary metabolic process regulation of macromolecule metabolic process gene expression translation macromolecule biosynthetic process regulation of cellular biosynthetic process regulation of gene expression biosynthetic process regulation of translation regulation of macromolecule biosynthetic process metabolic process macromolecule metabolic process regulation of metabolic process regulation of cellular component organization positive regulation of cellular component organization cell-substrate junction assembly positive regulation of cell-substrate junction organization positive regulation of biological process cellular component organization cellular component biogenesis cell adhesion cellular component assembly cell junction assembly positive regulation of cell-substrate adhesion regulation of cell-substrate junction organization cellular component organization or biogenesis positive regulation of cellular process focal adhesion assembly positive regulation of focal adhesion assembly positive regulation of cellular component biogenesis regulation of cell-substrate adhesion positive regulation of cell adhesion regulation of cell adhesion cell-substrate adhesion positive regulation of cell-matrix adhesion regulation of cellular component biogenesis regulation of cell junction assembly positive regulation of cell junction assembly cell junction organization cell-matrix adhesion regulation of cell-matrix adhesion cell-substrate junction organization regulation of focal adhesion assembly regulation of cell-substrate junction assembly cellular response to stimulus cellular response to nutrient levels response to nutrient levels cellular response to stress response to stress response to starvation cellular response to starvation embryonic epithelial tube formation chordate embryonic development tube formation embryo development epithelial tube formation tube morphogenesis primary neural tube formation embryo development ending in birth or egg hatching epithelial tube morphogenesis morphogenesis of embryonic epithelium epithelium development neural tube development tube development embryonic morphogenesis morphogenesis of an epithelium nervous system development anatomical structure morphogenesis tissue morphogenesis neural tube closure neural tube formation anatomical structure formation involved in morphogenesis tube closure head development forebrain development brain development pallium development cerebral cortex development central nervous system development telencephalon development signaling negative regulation of signaling negative regulation of intracellular signal transduction negative regulation of biological process regulation of signal transduction intracellular signal transduction negative regulation of cell communication cell communication negative regulation of TOR signaling regulation of intracellular signal transduction negative regulation of cellular process signal transduction TOR signaling regulation of signaling regulation of TOR signaling negative regulation of response to stimulus negative regulation of signal transduction regulation of response to stimulus regulation of cell communication kidney development renal system development hippocampus development limbic system development negative regulation of cellular metabolic process negative regulation of translation negative regulation of protein metabolic process negative regulation of macromolecule metabolic process negative regulation of metabolic process negative regulation of cellular biosynthetic process negative regulation of gene expression negative regulation of biosynthetic process negative regulation of macromolecule biosynthetic process adult locomotory behavior behavior adult behavior locomotory behavior immunological memory formation process cell development mononuclear cell differentiation lymphocyte activation lymphocyte differentiation cell activation involved in immune response leukocyte activation memory T cell differentiation T cell activation involved in immune response T cell activation leukocyte activation involved in immune response T cell differentiation lymphocyte activation involved in immune response hemopoiesis cell activation T cell differentiation involved in immune response immune effector process immunological memory process leukocyte differentiation regulation of cytoskeleton organization regulation of actin filament-based process regulation of actin filament bundle assembly actin filament bundle organization actin filament-based process stress fiber assembly regulation of actin filament organization actin cytoskeleton organization actomyosin structure organization actin filament organization regulation of organelle organization regulation of stress fiber assembly organelle organization contractile actin filament bundle assembly regulation of actomyosin structure organization actin filament bundle assembly regulation of actin cytoskeleton organization regulation of supramolecular fiber organization supramolecular fiber organization cytoskeleton organization negative regulation of cellular catabolic process catabolic process macroautophagy autophagy regulation of autophagy cellular catabolic process process utilizing autophagic mechanism negative regulation of catabolic process regulation of catabolic process negative regulation of macroautophagy regulation of macroautophagy negative regulation of autophagy regulation of cellular catabolic process synapse organization localization transport monoatomic ion transport potassium ion transport monoatomic cation transport establishment of localization metal ion transport response to decreased oxygen levels cellular response to chemical stimulus cellular response to oxygen levels response to chemical response to oxygen levels cellular response to decreased oxygen levels response to abiotic stimulus negative regulation of cell population proliferation regulation of cell population proliferation response to organic substance response to hormone response to endogenous stimulus response to organonitrogen compound response to peptide hormone response to insulin response to oxygen-containing compound response to nitrogen compound negative regulation of TORC1 signaling regulation of TORC1 signaling TORC1 signaling protein dephosphorylation regulation of phosphatase activity regulation of protein modification process regulation of catalytic activity regulation of phosphoprotein phosphatase activity regulation of phosphate metabolic process phosphate-containing compound metabolic process phosphorus metabolic process protein modification process regulation of dephosphorylation regulation of protein dephosphorylation dephosphorylation regulation of hydrolase activity macromolecule modification regulation of phosphorus metabolic process system process learning learning or memory nervous system process cognition associative learning activation of GTPase activity positive regulation of molecular function positive regulation of hydrolase activity positive regulation of catalytic activity regulation of GTPase activity positive regulation of GTPase activity myelination axon ensheathment ensheathment of neurons cell cycle regulation of cell cycle hexose transmembrane transport glucose import organic substance transport carbohydrate transport transmembrane transport glucose transmembrane transport monosaccharide transmembrane transport carbohydrate transmembrane transport cell projection organization negative regulation of cell size regulation of cellular component size regulation of cell size regulation of anatomical structure size	cell projection cell leading edge cellular anatomical entity plasma membrane bounded cell projection lamellipodium membrane intracellular anatomical structure cytoplasm cytosol protein-containing complex protein folding chaperone complex intracellular protein-containing complex vacuolar membrane membrane-bounded organelle cell projection cell leading edge cellular anatomical entity plasma membrane bounded cell projection lamellipodium membrane intracellular anatomical structure cytoplasm cytosol protein-containing complex protein folding chaperone complex intracellular protein-containing complex vacuolar membrane membrane-bounded organelle lytic vacuole vacuole intracellular membrane-bounded organelle intracellular organelle lytic vacuole membrane bounding membrane of organelle organelle lysosomal membrane organelle membrane lysosome perinuclear region of cytoplasm TSC1-TSC2 complex cell periphery cell cortex plasma membrane lipid droplet intracellular non-membrane-bounded organelle non-membrane-bounded organelle postsynaptic density postsynapse neuron to neuron synapse postsynaptic specialization synapse cell junction asymmetric synapse nucleus
B [auth A], C [auth B]	Isoform 7 of Tuberin	small GTPase binding protein binding binding enzyme binding GTPase binding Hsp90 protein binding heat shock protein binding GTPase regulator activity enzyme regulator activity enzyme activator activity GTPase activator activity molecular function activator activity nucleoside-triphosphatase regulator activity molecular function regulator activity small GTPase binding protein binding binding enzyme binding GTPase binding Hsp90 protein binding heat shock protein binding GTPase regulator activity enzyme regulator activity enzyme activator activity GTPase activator activity molecular function activator activity nucleoside-triphosphatase regulator activity molecular function regulator activity identical protein binding protein homodimerization activity protein dimerization activity phosphatase binding	negative regulation of cellular catabolic process catabolic process regulation of cellular process regulation of cellular component organization macroautophagy autophagy negative regulation of biological process regulation of autophagy negative regulation of cellular metabolic process cellular catabolic process cellular component organization mitophagy organelle disassembly negative regulation of cellular process negative regulation of cellular catabolic process catabolic process regulation of cellular process regulation of cellular component organization macroautophagy autophagy negative regulation of biological process regulation of autophagy negative regulation of cellular metabolic process cellular catabolic process cellular component organization mitophagy organelle disassembly negative regulation of cellular process regulation of autophagy of mitochondrion cellular component organization or biogenesis process utilizing autophagic mechanism mitochondrion organization cellular component disassembly negative regulation of catabolic process regulation of biological process negative regulation of cellular component organization cellular metabolic process negative regulation of metabolic process negative regulation of autophagy of mitochondrion biological regulation regulation of cellular metabolic process regulation of mitophagy regulation of catabolic process negative regulation of mitophagy regulation of organelle organization negative regulation of macroautophagy organelle organization regulation of macroautophagy negative regulation of organelle organization negative regulation of autophagy regulation of cellular catabolic process regulation of mitochondrion organization metabolic process cellular process regulation of metabolic process autophagy of mitochondrion developmental process heart development multicellular organism development multicellular organismal process anatomical structure development animal organ development circulatory system development system development cellular response to stimulus response to stimulus negative regulation of signaling signaling regulation of signal transduction negative regulation of cell communication cell communication negative regulation of Wnt signaling pathway signal transduction Wnt signaling pathway regulation of signaling cell surface receptor signaling pathway regulation of Wnt signaling pathway negative regulation of response to stimulus negative regulation of signal transduction regulation of response to stimulus regulation of cell communication protein localization localization cellular localization cellular macromolecule localization macromolecule localization intracellular signal transduction intracellular signaling cassette phosphatidylinositol 3-kinase/protein kinase B signal transduction regulation of localization import into cell regulation of transport transport regulation of vesicle-mediated transport establishment of localization vesicle-mediated transport endocytosis regulation of endocytosis positive chemotaxis chemotaxis taxis response to chemical response to external stimulus locomotion establishment of protein localization nitrogen compound transport nucleocytoplasmic transport nuclear transport organic substance transport intracellular transport protein localization to nucleus import into nucleus establishment of protein localization to organelle protein transport protein localization to organelle establishment of localization in cell protein import into nucleus intracellular protein transport insulin-like growth factor receptor signaling pathway cell surface receptor protein tyrosine kinase signaling pathway enzyme-linked receptor protein signaling pathway cellular response to nitrogen compound response to organic substance response to peptide hormone insulin receptor signaling pathway regulation of cellular response to insulin stimulus cellular response to endogenous stimulus response to hormone cellular response to organic substance cellular response to hormone stimulus response to endogenous stimulus response to organonitrogen compound regulation of insulin receptor signaling pathway response to oxygen-containing compound cellular response to peptide hormone stimulus response to nitrogen compound cellular response to oxygen-containing compound cellular response to chemical stimulus negative regulation of cellular response to insulin stimulus cellular response to organonitrogen compound negative regulation of insulin receptor signaling pathway response to insulin cellular response to insulin stimulus cellular response to nutrient levels response to nutrient levels cellular response to stress response to stress response to starvation cellular response to starvation embryonic epithelial tube formation chordate embryonic development tube formation embryo development epithelial tube formation tube morphogenesis primary neural tube formation embryo development ending in birth or egg hatching epithelial tube morphogenesis morphogenesis of embryonic epithelium epithelium development neural tube development tube development embryonic morphogenesis morphogenesis of an epithelium nervous system development tissue development anatomical structure morphogenesis tissue morphogenesis neural tube closure neural tube formation anatomical structure formation involved in morphogenesis tube closure regulation of catalytic activity negative regulation of catalytic activity regulation of transferase activity regulation of primary metabolic process negative regulation of kinase activity negative regulation of transferase activity regulation of phosphate metabolic process phosphate-containing compound metabolic process negative regulation of protein modification process phosphorus metabolic process protein modification process negative regulation of protein metabolic process protein phosphorylation phosphorylation regulation of protein metabolic process primary metabolic process regulation of molecular function regulation of kinase activity negative regulation of protein phosphorylation macromolecule modification regulation of phosphorus metabolic process macromolecule metabolic process regulation of protein modification process regulation of protein phosphorylation negative regulation of phosphate metabolic process organic substance metabolic process protein metabolic process negative regulation of macromolecule metabolic process organonitrogen compound metabolic process negative regulation of molecular function negative regulation of protein kinase activity regulation of protein kinase activity regulation of macromolecule metabolic process negative regulation of phosphorus metabolic process regulation of phosphorylation negative regulation of phosphorylation negative regulation of intracellular signal transduction negative regulation of TOR signaling regulation of intracellular signal transduction TOR signaling regulation of TOR signaling positive regulation of biological process positive regulation of cellular metabolic process positive regulation of metabolic process positive regulation of macroautophagy positive regulation of cellular process positive regulation of autophagy positive regulation of catabolic process positive regulation of cellular catabolic process negative regulation of cell population proliferation cell population proliferation regulation of cell population proliferation regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction small GTPase-mediated signal transduction regulation of small GTPase mediated signal transduction negative regulation of TORC1 signaling regulation of TORC1 signaling TORC1 signaling cell cycle regulation of cell cycle anoikis apoptotic process cell death programmed cell death	protein-containing complex intracellular anatomical structure TSC1-TSC2 complex cytoplasm cellular anatomical entity cytosol membrane membrane-bounded organelle intracellular organelle organelle lytic vacuole vacuole intracellular membrane-bounded organelle lysosome protein-containing complex intracellular anatomical structure TSC1-TSC2 complex cytoplasm cellular anatomical entity cytosol membrane membrane-bounded organelle intracellular organelle organelle lytic vacuole vacuole intracellular membrane-bounded organelle lysosome vacuolar membrane lytic vacuole membrane bounding membrane of organelle lysosomal membrane organelle membrane Golgi apparatus endomembrane system postsynaptic density postsynapse neuron to neuron synapse postsynaptic specialization synapse cell junction asymmetric synapse perinuclear region of cytoplasm nucleus
E	TBC1 domain family member 7	small GTPase binding protein binding binding enzyme binding GTPase binding GTPase regulator activity enzyme regulator activity enzyme activator activity GTPase activator activity molecular function activator activity nucleoside-triphosphatase regulator activity molecular function regulator activity	cellular response to stimulus cellular response to nutrient levels response to nutrient levels response to stimulus cellular response to stress response to stress cellular process response to starvation cellular response to starvation regulation of cellular process signaling negative regulation of signaling negative regulation of intracellular signal transduction negative regulation of biological process cellular response to stimulus cellular response to nutrient levels response to nutrient levels response to stimulus cellular response to stress response to stress cellular process response to starvation cellular response to starvation regulation of cellular process signaling negative regulation of signaling negative regulation of intracellular signal transduction negative regulation of biological process regulation of signal transduction intracellular signal transduction negative regulation of cell communication cell communication negative regulation of TOR signaling regulation of intracellular signal transduction negative regulation of cellular process signal transduction TOR signaling regulation of biological process regulation of signaling regulation of TOR signaling negative regulation of response to stimulus biological regulation negative regulation of signal transduction regulation of response to stimulus regulation of cell communication response to endogenous stimulus response to growth factor negative regulation of TORC1 signaling regulation of TORC1 signaling TORC1 signaling positive regulation of molecular function regulation of molecular function positive regulation of hydrolase activity regulation of catalytic activity regulation of hydrolase activity positive regulation of catalytic activity regulation of GTPase activity positive regulation of GTPase activity activation of GTPase activity regulation of protein modification process positive regulation of protein metabolic process positive regulation of biological process regulation of protein ubiquitination positive regulation of post-translational protein modification regulation of primary metabolic process positive regulation of metabolic process positive regulation of protein modification process organic substance metabolic process protein ubiquitination positive regulation of macromolecule metabolic process protein metabolic process regulation of protein modification by small protein conjugation or removal protein modification process positive regulation of protein modification by small protein conjugation or removal positive regulation of protein ubiquitination organonitrogen compound metabolic process regulation of post-translational protein modification regulation of protein metabolic process primary metabolic process regulation of macromolecule metabolic process macromolecule modification metabolic process macromolecule metabolic process post-translational protein modification regulation of metabolic process protein modification by small protein conjugation protein modification by small protein conjugation or removal regulation of cellular component organization cell projection organization negative regulation of organelle assembly plasma membrane bounded cell projection assembly cellular component biogenesis cellular component organization negative regulation of plasma membrane bounded cell projection assembly cellular component assembly cilium assembly cellular component organization or biogenesis negative regulation of cell projection organization cilium organization organelle assembly plasma membrane bounded cell projection organization negative regulation of cellular component organization regulation of cell projection organization regulation of cell projection assembly regulation of cellular component biogenesis regulation of organelle organization regulation of plasma membrane bounded cell projection assembly organelle organization regulation of cilium assembly negative regulation of organelle organization regulation of organelle assembly negative regulation of cilium assembly cell projection assembly regulation of plasma membrane bounded cell projection organization	membrane-bounded organelle intracellular organelle intracellular anatomical structure cytoplasmic vesicle organelle intracellular vesicle cytoplasm cellular anatomical entity intracellular membrane-bounded organelle vesicle protein-containing complex TSC1-TSC2 complex cytosol vacuolar membrane membrane-bounded organelle intracellular organelle intracellular anatomical structure cytoplasmic vesicle organelle intracellular vesicle cytoplasm cellular anatomical entity intracellular membrane-bounded organelle vesicle protein-containing complex TSC1-TSC2 complex cytosol vacuolar membrane membrane lytic vacuole vacuole lytic vacuole membrane bounding membrane of organelle lysosomal membrane organelle membrane lysosome cilium plasma membrane bounded cell projection ciliary basal body cell projection microtubule organizing center cytoskeleton intracellular non-membrane-bounded organelle microtubule cytoskeleton non-membrane-bounded organelle
F	unknown protein	-	-	-

InterPro: Protein Family Classification InterPro Database Homepage

Chains	Accession	Name	Type
A [auth D], D [auth C]	IPR007483	Hamartin	Family
B [auth A], C [auth B]	IPR016024	Armadillo-type fold	Homologous Superfamily
B [auth A], C [auth B]	IPR011989	Armadillo-like helical	Homologous Superfamily
B [auth A], C [auth B]	IPR024584	Tuberin, N-terminal	Domain
B [auth A], C [auth B]	IPR000331	Rap/Ran-GAP domain	Domain
B [auth A], C [auth B]	IPR027107	Tuberin/Ral GTPase-activating protein subunit alpha	Family
B [auth A], C [auth B]	IPR018515	Tuberin-type domain	Domain
B [auth A], C [auth B]	IPR035974	Rap/Ran-GAP superfamily	Homologous Superfamily
B [auth A], C [auth B]	IPR003913	Tuberin	Family
E	IPR035969	Rab-GAP-TBC domain superfamily	Homologous Superfamily
E	IPR043039	TBC1 domain family member 7, domain 2	Homologous Superfamily
E	IPR039842	TBC1 domain family member 7	Family
E	IPR000195	Rab-GAP-TBC domain	Domain

Pharos: Disease Associations Pharos Homepage Annotation

Chains	Drug Target	Associated Disease
A [auth D], D [auth C]	Pharos: Q92574	tuberous sclerosis lung lymphangioleiomyomatosis squamous cell carcinoma renal cell carcinoma epilepsy progressive myoclonus epilepsy isolated focal cortical dysplasia type II tuberous sclerosis 1 Cognition Disorders dentatorubral-pallidoluysian atrophy West syndrome brain disease chromophobe renal cell carcinoma collecting duct carcinoma lymphangioleiomyomatosis tuberous sclerosis lung lymphangioleiomyomatosis squamous cell carcinoma renal cell carcinoma epilepsy progressive myoclonus epilepsy isolated focal cortical dysplasia type II tuberous sclerosis 1 Cognition Disorders dentatorubral-pallidoluysian atrophy West syndrome brain disease chromophobe renal cell carcinoma collecting duct carcinoma lymphangioleiomyomatosis developmental and epileptic encephalopathy sarcomatoid renal cell carcinoma visual epilepsy papillary renal cell carcinoma intellectual disability malignant ependymoma urinary bladder neoplasm neoplasm angiomyolipoma atypical teratoid rhabdoid tumor oral cavity neoplasm hepatocellular carcinoma large cell medulloblastoma malignant glioma urinary bladder cancer action myoclonus-renal failure syndrome ovarian cancer renal carcinoma bladder benign neoplasm glioblastoma cancer clear cell renal carcinoma Spasmus nutans Ehlers-Danlos syndrome urinary bladder carcinoma adult hepatocellular carcinoma autism benign urinary system neoplasm bladder carcinoma in situ cholangiocarcinoma
B [auth A], C [auth B]	Pharos: P49815	tuberous sclerosis squamous cell carcinoma lung lymphangioleiomyomatosis epilepsy tuberous sclerosis 2 acute myeloid leukemia cancer lymphangioleiomyomatosis Mouth Neoplasms autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis brain disease intellectual disability leiomyoma visual epilepsy autism tuberous sclerosis squamous cell carcinoma lung lymphangioleiomyomatosis epilepsy tuberous sclerosis 2 acute myeloid leukemia cancer lymphangioleiomyomatosis Mouth Neoplasms autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis brain disease intellectual disability leiomyoma visual epilepsy autism isolated focal cortical dysplasia type II kidney cancer developmental and epileptic encephalopathy uterine corpus leiomyoma West syndrome subependymal giant cell astrocytoma kidney neoplasm dilated cardiomyopathy pancreatic neoplasm astrocytic tumor head and neck squamous cell carcinoma Spasmus nutans tuberous sclerosis 1 Ehlers-Danlos syndrome oral cavity neoplasm adult hepatocellular carcinoma precancerous condition thyroid gland carcinoma malignant pancreatic neoplasm ovarian cancer angiomyolipoma atrial fibrillation benign urinary system neoplasm
E	Pharos: Q9P0N9	acute myeloid leukemia Macrocephaly ovarian cancer tuberculosis hydrocephalus macrocephaly/megalencephaly syndrome, autosomal recessive pancreatic ductal adenocarcinoma invasive ductal breast carcinoma non-small cell lung carcinoma pancreatic intraductal papillary-mucinous carcinoma

RCSB PDB Core Operations are funded by the U.S. National Science Foundation (DBI-2321666), the US Department of Energy (DE-SC0019749), and the National Cancer Institute, National Institute of Allergy and Infectious Diseases, and National Institute of General Medical Sciences of the National Institutes of Health under grant R01GM133198.