6XMJ

Human 20S proteasome bound to an engineered 11S (PA26) activator


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.00 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

The Y Phi motif defines the structure-activity relationships of human 20S proteasome activators.

Opoku-Nsiah, K.A.de la Pena, A.H.Williams, S.K.Chopra, N.Sali, A.Lander, G.C.Gestwicki, J.E.

(2022) Nat Commun 13: 1226-1226

  • DOI: https://doi.org/10.1038/s41467-022-28864-x
  • Primary Citation of Related Structures:  
    6XMJ

  • PubMed Abstract: 

    The 20S proteasome (20S) facilitates turnover of most eukaryotic proteins. Substrate entry into the 20S first requires opening of gating loops through binding of HbYX motifs that are present at the C-termini of certain proteasome activators (PAs). The HbYX motif has been predominantly characterized in the archaeal 20S, whereas little is known about the sequence preferences of the human 20S (h20S). Here, we synthesize and screen ~120 HbYX-like peptides, revealing unexpected differences from the archaeal system and defining the h20S recognition sequence as the Y-F/Y (YФ) motif. To gain further insight, we create a functional chimera of the optimized sequence, NLSYYT, fused to the model activator, PA26 E102A . A cryo-EM structure of PA26 E102A -h20S is used to identify key interactions, including non-canonical contacts and gate-opening mechanisms. Finally, we demonstrate that the YФ sequence preferences are tuned by valency, allowing multivalent PAs to sample greater sequence space. These results expand the model for termini-mediated gating and provide a template for the design of h20S activators.


  • Organizational Affiliation

    Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-6244Homo sapiensMutation(s): 0 
Gene Names: PSMA6PROS27
EC: 3.4.25.1
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PHAROS:  P60900
GTEx:  ENSG00000100902 
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UniProt GroupP60900
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-2233Homo sapiensMutation(s): 0 
Gene Names: PSMA2HC3PSC3
EC: 3.4.25.1
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PHAROS:  P25787
GTEx:  ENSG00000106588 
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UniProt GroupP25787
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-4250Homo sapiensMutation(s): 0 
Gene Names: PSMA4HC9PSC9
EC: 3.4.25.1
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GTEx:  ENSG00000041357 
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UniProt GroupP25789
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-7243Homo sapiensMutation(s): 0 
Gene Names: PSMA7HSPC
EC: 3.4.25.1
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GTEx:  ENSG00000101182 
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UniProt GroupO14818
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Entity ID: 5
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-5234Homo sapiensMutation(s): 0 
Gene Names: PSMA5
EC: 3.4.25.1
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GTEx:  ENSG00000143106 
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Entity ID: 6
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-1238Homo sapiensMutation(s): 0 
Gene Names: PSMA1HC2NUPROS30PSC2
EC: 3.4.25.1
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GTEx:  ENSG00000129084 
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Entity ID: 7
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-3245Homo sapiensMutation(s): 0 
Gene Names: PSMA3HC8PSC8
EC: 3.4.25.1
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GTEx:  ENSG00000100567 
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Entity ID: 8
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-6202Homo sapiensMutation(s): 0 
Gene Names: PSMB6LMPYY
EC: 3.4.25.1
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GTEx:  ENSG00000142507 
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Entity ID: 9
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-7220Homo sapiensMutation(s): 0 
Gene Names: PSMB7Z
EC: 3.4.25.1
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GTEx:  ENSG00000136930 
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Entity ID: 10
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-3204Homo sapiensMutation(s): 0 
Gene Names: PSMB3
EC: 3.4.25.1
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GTEx:  ENSG00000277791 
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Entity ID: 11
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-2199Homo sapiensMutation(s): 0 
Gene Names: PSMB2
EC: 3.4.25.1
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GTEx:  ENSG00000126067 
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Entity ID: 12
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-5201Homo sapiensMutation(s): 0 
Gene Names: PSMB5LMPXMB1X
EC: 3.4.25.1
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GTEx:  ENSG00000100804 
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Entity ID: 13
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-1213Homo sapiensMutation(s): 0 
Gene Names: PSMB1PSC5
EC: 3.4.25.1
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GTEx:  ENSG00000008018 
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Entity ID: 14
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-4217Homo sapiensMutation(s): 0 
Gene Names: PSMB4PROS26
EC: 3.4.25.1
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GTEx:  ENSG00000159377 
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Entity ID: 15
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome activator protein PA26
O, P, Q, R, S
O, P, Q, R, S, T, U
228Trypanosoma bruceiMutation(s): 3 
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Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.00 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 
EM Software:
TaskSoftware PackageVersion
RECONSTRUCTIONRELION2.1
MODEL REFINEMENTPHENIX1.11-2580

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesDP2-EB020402
American Cancer SocietyUnited States132279-PF-18-189-01- DMC

Revision History  (Full details and data files)

  • Version 1.0: 2020-07-22
    Type: Initial release
  • Version 1.1: 2022-03-23
    Changes: Database references
  • Version 1.2: 2024-05-15
    Changes: Data collection