9D1Z

Structure of G75Q Ubiquitin bound to KLHDC3-EloB/C

Summary for 9D1Z

• Entry DOI: 10.2210/pdb9d1z/pdb
• Descriptor: Kelch domain-containing protein 3, Elongin-B, Elongin-C, ... (6 entities in total)
• Functional Keywords: klhdc3, ubiquitin, c-degron, cullin-ring, e3, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 77985.70

Authors

Schulman, B.A.,Scott, D.C. (deposition date: 2024-08-08, release date: 2024-11-20, Last modification date: 2025-02-05)

Primary citation

Scott, D.C.,Chittori, S.,Purser, N.,King, M.T.,Maiwald, S.A.,Churion, K.,Nourse, A.,Lee, C.,Paulo, J.A.,Miller, D.J.,Elledge, S.J.,Harper, J.W.,Kleiger, G.,Schulman, B.A.
Structural basis for C-degron selectivity across KLHDCX family E3 ubiquitin ligases.
Nat Commun, 15:9899-9899, 2024

PubMed Abstract: Specificity of the ubiquitin-proteasome system depends on E3 ligase-substrate interactions. Many such pairings depend on E3 ligases binding to peptide-like sequences - termed N- or C-degrons - at the termini of substrates. However, our knowledge of structural features distinguishing closely related C-degron substrate-E3 pairings is limited. Here, by systematically comparing ubiquitylation activities towards a suite of common model substrates, and defining interactions by biochemistry, crystallography, and cryo-EM, we reveal principles of C-degron recognition across the KLHDCX family of Cullin-RING ligases (CRLs). First, a motif common across these E3 ligases anchors a substrate's C-terminus. However, distinct locations of this C-terminus anchor motif in different blades of the KLHDC2, KLHDC3, and KLHDC10 β-propellers establishes distinct relative positioning and molecular environments for substrate C-termini. Second, our structural data show KLHDC3 has a pre-formed pocket establishing preference for an Arg or Gln preceding a C-terminal Gly, whereas conformational malleability contributes to KLHDC10's recognition of varying features adjacent to substrate C-termini. Finally, additional non-consensus interactions, mediated by C-degron binding grooves and/or by distal propeller surfaces and substrate globular domains, can substantially impact substrate binding and ubiquitylatability. Overall, the data reveal combinatorial mechanisms determining specificity and plasticity of substrate recognition by KLDCX-family C-degron E3 ligases.

PubMed: 39548056
DOI: 10.1038/s41467-024-54126-z

Experimental method

X-RAY DIFFRACTION (1.88 Å)