4WJ7

CCM2 PTB domain in complex with KRIT1 NPxY/F3


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.75 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.222 

wwPDB Validation   3D Report Full Report


This is version 1.5 of the entry. See complete history


Literature

Structural Basis for the Disruption of the Cerebral Cavernous Malformations 2 (CCM2) Interaction with Krev Interaction Trapped 1 (KRIT1) by Disease-associated Mutations.

Fisher, O.S.Liu, W.Zhang, R.Stiegler, A.L.Ghedia, S.Weber, J.L.Boggon, T.J.

(2015) J Biol Chem 290: 2842-2853

  • DOI: https://doi.org/10.1074/jbc.M114.616433
  • Primary Citation of Related Structures:  
    4WJ7

  • PubMed Abstract: 

    Familial cerebral cavernous malformations (CCMs) are predominantly neurovascular lesions and are associated with mutations within the KRIT1, CCM2, and PDCD10 genes. The protein products of KRIT1 and CCM2 (Krev interaction trapped 1 (KRIT1) and cerebral cavernous malformations 2 (CCM2), respectively) directly interact with each other. Disease-associated mutations in KRIT1 and CCM2 mostly result in loss of their protein products, although rare missense point mutations can also occur. From gene sequencing of patients known or suspected to have one or more CCMs, we discover a series of missense point mutations in KRIT1 and CCM2 that result in missense mutations in the CCM2 and KRIT1 proteins. To place these mutations in the context of the molecular level interactions of CCM2 and KRIT1, we map the interaction of KRIT1 and CCM2 and find that the CCM2 phosphotyrosine binding (PTB) domain displays a preference toward the third of the three KRIT1 NPX(Y/F) motifs. We determine the 2.75 Å co-crystal structure of the CCM2 PTB domain with a peptide corresponding to KRIT1(NPX(Y/F)3), revealing a Dab-like PTB fold for CCM2 and its interaction with KRIT1(NPX(Y/F)3). We find that several disease-associated missense mutations in CCM2 have the potential to interrupt the KRIT1-CCM2 interaction by destabilizing the CCM2 PTB domain and that a KRIT1 mutation also disrupts this interaction. We therefore provide new insights into the architecture of CCM2 and how the CCM complex is disrupted in CCM disease.


  • Organizational Affiliation

    From the Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Malcavernin
A, B, C, D
180Homo sapiensMutation(s): 0 
Gene Names: CCM2C7orf22PP10187
UniProt & NIH Common Fund Data Resources
Find proteins for Q9BSQ5 (Homo sapiens)
Explore Q9BSQ5 
Go to UniProtKB:  Q9BSQ5
PHAROS:  Q9BSQ5
GTEx:  ENSG00000136280 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9BSQ5
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
KRIT1 NPxY/F3E [auth W],
F [auth X],
G [auth Y],
H [auth Z]
13Homo sapiensMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

Unit Cell:
Length ( Å )Angle ( ˚ )
a = 110.938α = 90
b = 110.938β = 90
c = 315.255γ = 120
Software Package:
Software NamePurpose
HKL-2000data scaling
PDB_EXTRACTdata extraction
PHENIXrefinement

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)United StatesR01NS085078

Revision History  (Full details and data files)

  • Version 1.0: 2014-12-24
    Type: Initial release
  • Version 1.1: 2014-12-31
    Changes: Database references
  • Version 1.2: 2015-02-11
    Changes: Database references
  • Version 1.3: 2017-09-27
    Changes: Author supporting evidence, Database references, Derived calculations, Other, Refinement description, Source and taxonomy, Structure summary
  • Version 1.4: 2019-12-18
    Changes: Author supporting evidence
  • Version 1.5: 2023-09-27
    Changes: Data collection, Database references, Refinement description