4abm
Crystal Structure of CHMP4B hairpin
Structural highlights
DiseaseCHM4B_HUMAN Defects in CHMP4B are the cause of cataract posterior polar type 3 (CTPP3) [MIM:605387. A subcapsular opacity, usually disk-shaped, located at the back of the lens. It can have a marked effect on visual acuity.[1] FunctionCHM4B_HUMAN Probable core component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. The MVB pathway appears to require the sequential function of ESCRT-O, -I,-II and -III complexes. ESCRT-III proteins mostly dissociate from the invaginating membrane before the ILV is released. The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and the budding of enveloped viruses (HIV-1 and other lentiviruses). ESCRT-III proteins are believed to mediate the necessary vesicle extrusion and/or membrane fission activities, possibly in conjunction with the AAA ATPase VPS4. When overexpressed, membrane-assembled circular arrays of CHMP4B filaments can promote or stabilize negative curvature and outward budding. Via its interaction with PDCD6IP involved in HIV-1 p6- and p9-dependent virus release.[2] [3] [4] [5] [6] Publication Abstract from PubMedEndosomal sorting complexes required for transport (ESCRTs) regulate diverse processes ranging from receptor sorting at endosomes to distinct steps in cell division and budding of some enveloped viruses. Common to all processes is the membrane recruitment of ESCRT-III that leads to membrane fission. Here, we show that CC2D1A is a novel regulator of ESCRT-III CHMP4B function. We demonstrate that CHMP4B interacts directly with CC2D1A and CC2D1B with nanomolar affinity by forming a 1:1 complex. Deletion mapping revealed a minimal CC2D1A-CHMP4B binding construct, which includes a short linear sequence within the third DM14 domain of CC2D1A. The CC2D1A binding site on CHMP4B was mapped to the N-terminal helical hairpin. Based on a crystal structure of the CHMP4B helical hairpin, two surface patches were identified that interfere with CC2D1A interaction as determined by surface plasmon resonance. Introducing these mutations into a C-terminal truncation of CHMP4B that exerts a potent dominant negative effect on human immunodeficiency virus type 1 budding revealed that one of the mutants lost this effect completely. This suggests that the identified CC2D1A binding surface might be required for CHMP4B polymerization, which is consistent with the finding that CC2D1A binding to CHMP4B prevents CHMP4B polymerization in vitro. Thus, CC2D1A might act as a negative regulator of CHMP4B function. CC2D1A Is a Regulator of ESCRT-III CHMP4B.,Martinelli N, Hartlieb B, Usami Y, Sabin C, Dordor A, Miguet N, Avilov SV, Ribeiro EA Jr, Gottlinger H, Weissenhorn W J Mol Biol. 2012 May 25;419(1-2):75-88. Epub 2012 Mar 8. PMID:22406677[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also
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