5lp8
Crystal structure of an asymmetric dimer of the ubiquitin ligase HUWE1
Structural highlights
DiseaseHUWE1_HUMAN Defects in HUWE1 are the cause of mental retardation syndromic X-linked Turner type (MRXST) [MIM:300706; also known as mental retardation and macrocephaly syndrome. MRXST shows clinical variability. Associated phenotypes include macrocephaly and variable contractures. A chromosomal microduplication involving HUWE1 and HSD17B10 is the cause of mental retardation X-linked type 17 (MRX17) [MIM:300705; also known as mental retardation X-linked type 31 (MRX31). Mental retardation is characterized by significantly sub-average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period. In contrast to syndromic or specific X-linked mental retardation which also present with associated physical, neurological and/or psychiatric manifestations, intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation.[1] FunctionHUWE1_HUMAN E3 ubiquitin-protein ligase which mediates ubiquitination and subsequent proteasomal degradation of target proteins. Regulates apoptosis by catalyzing the polyubiquitination and degradation of MCL1. Mediates monoubiquitination of DNA polymerase beta (POLB) at 'Lys-41', 'Lys-61' and 'Lys-81', thereby playing a role in base-excision repair. Also ubiquitinates the p53/TP53 tumor suppressor and core histones including H1, H2A, H2B, H3 and H4. Binds to an upstream initiator-like sequence in the preprodynorphin gene. Regulates neural differentiation and proliferation by catalyzing the polyubiquitination and degradation of MYCN. May regulate abundance of CDC6 after DNA damage by polyubiquitinating and targeting CDC6 to degradation.[2] [3] [4] [5] [6] [7] [8] Publication Abstract from PubMedThe human ubiquitin ligase HUWE1 has key roles in tumorigenesis, yet it is unkown how its activity is regulated. We present the crystal structure of a C-terminal part of HUWE1, including the catalytic domain, and reveal an asymmetric auto-inhibited dimer. We show that HUWE1 dimerizes in solution and self-associates in cells, and that both occurs through the crystallographic dimer interface. We demonstrate that HUWE1 is inhibited in cells and that it can be activated by disruption of the dimer interface. We identify a conserved segment in HUWE1 that counteracts dimer formation by associating with the dimerization region intramolecularly. Our studies reveal, intriguingly, that the tumor suppressor p14ARF binds to this segment and may thus shift the conformational equilibrium of HUWE1 toward the inactive state. We propose a model, in which the activity of HUWE1 underlies conformational control in response to physiological cues-a mechanism that may be exploited for cancer therapy. A conformational switch regulates the ubiquitin ligase HUWE1.,Sander B, Xu W, Eilers M, Popov N, Lorenz S Elife. 2017 Feb 14;6. pii: e21036. doi: 10.7554/eLife.21036. PMID:28193319[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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