| Structural highlights
Disease
[KCD17_HUMAN] The disease is caused by mutations affecting the gene represented in this entry.
Function
[KCD17_HUMAN] Is a positive regulator of ciliogenesis, playing a crucial role in the initial steps of axoneme extension. It acts as a substrate-adapter for CUL3-RING ubiquitin ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of TCHP, a protein involved in ciliogenesis down-regulation (PubMed:25270598). May be involved in endoplasmic reticulum calcium ion homeostasis (PubMed:25983243).[1] [2]
Publication Abstract from PubMed
Members of the potassium channel tetramerization domain (KCTD) family are soluble non-channel proteins that commonly function as Cullin3 (Cul3)-dependent E3 ligases. Solution studies of the N-terminal BTB domain have suggested that some KCTD family members may tetramerize similarly to the homologous tetramerization domain (T1) of the voltage-gated potassium (Kv) channels. However, available structures of KCTD1, KCTD5 and KCTD9 have demonstrated instead pentameric assemblies. To explore other phylogenetic clades within the KCTD family, we determined the crystal structures of the BTB domains of a further five human KCTD proteins revealing a rich variety of oligomerization architectures, including monomer (SHKBP1), a novel two-fold symmetric tetramer (KCTD10 and KCTD13), open pentamer (KCTD16) and closed pentamer (KCTD17). While these diverse geometries were confirmed by small-angle X-ray scattering (SAXS), only the pentameric forms were stable upon size-exclusion chromatography. With the exception of KCTD16, all proteins bound to Cul3 and were observed to reassemble in solution as 5 : 5 heterodecamers. SAXS data and structural modelling indicate that Cul3 may stabilize closed BTB pentamers by binding across their BTB-BTB interfaces. These extra interactions likely also allow KCTD proteins to bind Cul3 without the expected 3-box motif. Overall, these studies reveal the KCTD family BTB domain to be a highly versatile scaffold compatible with a range of oligomeric assemblies and geometries. This observed interface plasticity may support functional changes in regulation of this unusual E3 ligase family.
Structural complexity in the KCTD family of Cullin3-dependent E3 ubiquitin ligases.,Pinkas DM, Sanvitale CE, Bufton JC, Sorrell FJ, Solcan N, Chalk R, Doutch J, Bullock AN Biochem J. 2017 Nov 1;474(22):3747-3761. doi: 10.1042/BCJ20170527. PMID:28963344[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kasahara K, Kawakami Y, Kiyono T, Yonemura S, Kawamura Y, Era S, Matsuzaki F, Goshima N, Inagaki M. Ubiquitin-proteasome system controls ciliogenesis at the initial step of axoneme extension. Nat Commun. 2014 Oct 1;5:5081. doi: 10.1038/ncomms6081. PMID:25270598 doi:https://dx.doi.org/10.1038/ncomms6081
- ↑ Mencacci NE, Rubio-Agusti I, Zdebik A, Asmus F, Ludtmann MH, Ryten M, Plagnol V, Hauser AK, Bandres-Ciga S, Bettencourt C, Forabosco P, Hughes D, Soutar MM, Peall K, Morris HR, Trabzuni D, Tekman M, Stanescu HC, Kleta R, Carecchio M, Zorzi G, Nardocci N, Garavaglia B, Lohmann E, Weissbach A, Klein C, Hardy J, Pittman AM, Foltynie T, Abramov AY, Gasser T, Bhatia KP, Wood NW. A missense mutation in KCTD17 causes autosomal dominant myoclonus-dystonia. Am J Hum Genet. 2015 Jun 4;96(6):938-47. doi: 10.1016/j.ajhg.2015.04.008. Epub, 2015 May 14. PMID:25983243 doi:https://dx.doi.org/10.1016/j.ajhg.2015.04.008
- ↑ Pinkas DM, Sanvitale CE, Bufton JC, Sorrell FJ, Solcan N, Chalk R, Doutch J, Bullock AN. Structural complexity in the KCTD family of Cullin3-dependent E3 ubiquitin ligases. Biochem J. 2017 Nov 1;474(22):3747-3761. doi: 10.1042/BCJ20170527. PMID:28963344 doi:https://dx.doi.org/10.1042/BCJ20170527
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