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7ep5

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Crystal structure of ZER1 bound to GKLH degron

Structural highlights

7ep5 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.02Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ZER1_HUMAN Serves as substrate adapter subunit in the E3 ubiquitin ligase complex ZYG11B-CUL2-Elongin BC (PubMed:17304241, PubMed:31273098). Acts redudantly with ZYG11B to target substrates bearing N-terminal glycine degrons for proteasomal degradation (PubMed:33093214). Involved in the clearance of proteolytic fragments generated by caspase cleavage during apoptosis since N-terminal glycine degrons are strongly enriched at caspase cleavage sites. Also important in the quality control of protein N-myristoylation in which N-terminal glycine degrons are conditionally exposed after a failure of N-myristoylation (PubMed:31273098).^[1] ^[2] ^[3]

Publication Abstract from PubMed

N-degron pathways are a set of proteolytic systems that target the N-terminal destabilizing residues of substrates for proteasomal degradation. Recently, the Gly/N-degron pathway has been identified as a new branch of the N-degron pathway. The N-terminal glycine degron (Gly/N-degron) is recognized by ZYG11B and ZER1, the substrate receptors of the Cullin 2-RING E3 ubiquitin ligase (CRL2). Here we present the crystal structures of ZYG11B and ZER1 bound to various Gly/N-degrons. The structures reveal that ZYG11B and ZER1 utilize their armadillo (ARM) repeats forming a deep and narrow cavity to engage mainly the first four residues of Gly/N-degrons. The alpha-amino group of the Gly/N-degron is accommodated in an acidic pocket by five conserved hydrogen bonds. These structures, together with biochemical studies, decipher the molecular basis for the specific recognition of the Gly/N-degron by ZYG11B and ZER1, providing key information for future structure-based chemical probe design.

Molecular basis for recognition of Gly/N-degrons by CRL2(ZYG11B) and CRL2(ZER1).,Yan X, Li Y, Wang G, Zhou Z, Song G, Feng Q, Zhao Y, Mi W, Ma Z, Dong C Mol Cell. 2021 Jun 23. pii: S1097-2765(21)00457-3. doi:, 10.1016/j.molcel.2021.06.010. PMID:34214466^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Vasudevan S, Starostina NG, Kipreos ET. The Caenorhabditis elegans cell-cycle regulator ZYG-11 defines a conserved family of CUL-2 complex components. EMBO Rep. 2007 Mar;8(3):279-86. Epub 2007 Feb 16. PMID:17304241 doi:http://dx.doi.org/7400895
↑ Timms RT, Zhang Z, Rhee DY, Harper JW, Koren I, Elledge SJ. A glycine-specific N-degron pathway mediates the quality control of protein N-myristoylation. Science. 2019 Jul 5;365(6448):eaaw4912. doi: 10.1126/science.aaw4912. PMID:31273098 doi:http://dx.doi.org/10.1126/science.aaw4912
↑ Robinson KS, Teo DET, Tan KS, Toh GA, Ong HH, Lim CK, Lay K, Au BV, Lew TS, Chu JJH, Chow VTK, Wang Y, Zhong FL, Reversade B. Enteroviral 3C protease activates the human NLRP1 inflammasome in airway epithelia. Science. 2020 Dec 4;370(6521):eaay2002. doi: 10.1126/science.aay2002. Epub 2020 , Oct 22. PMID:33093214 doi:http://dx.doi.org/10.1126/science.aay2002
↑ Yan X, Li Y, Wang G, Zhou Z, Song G, Feng Q, Zhao Y, Mi W, Ma Z, Dong C. Molecular basis for recognition of Gly/N-degrons by CRL2(ZYG11B) and CRL2(ZER1). Mol Cell. 2021 Aug 19;81(16):3262-3274.e3. PMID:34214466 doi:10.1016/j.molcel.2021.06.010