3tac
From Proteopedia
Crystal Structure of the Liprin-alpha/CASK complex
Structural highlights
Disease[CSKP_HUMAN] Defects in CASK are the cause of mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH) [MIM:300749]. A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period. Patients with mental retardation X-linked CASK-related can manifest a severe phenotype consisting of severe intellectual deficit, congenital or postnatal microcephaly, disproportionate brainstem and cerebellar hypoplasia. A milder phenotype consists of mental retardation alone or associated with nystagmus.[1] Defects in CASK are the cause of FG syndrome type 4 (FGS4) [MIM:300422]. FG syndrome (FGS) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation.[2] Function[CSKP_HUMAN] Multidomain scaffolding protein with a role in synaptic transmembrane protein anchoring and ion channel trafficking. Contributes to neural development and regulation of gene expression via interaction with the transcription factor TRB1. Binds to cell-surface proteins, including amyloid precursor protein, neurexins and syndecans. May mediate a link between the extracellular matrix and the actin cytoskeleton via its interaction with syndecan and with the actin/spectrin-binding protein 4.1. [LIPA2_HUMAN] Alters PTPRF cellular localization and induces PTPRF clustering. May regulate the disassembly of focal adhesions. May localize receptor-like tyrosine phosphatases type 2A at specific sites on the plasma membrane, possibly regulating their interaction with the extracellular environment and their association with substrates.[3] Publication Abstract from PubMedLiprins are highly conserved scaffold proteins that regulate cell adhesion, cell migration, and synapse development by binding to diverse target proteins. The molecular basis governing liprin/target interactions is poorly understood. The liprin-alpha2/CASK complex structure solved here reveals that the three SAM domains of liprin-alpha form an integrated supramodule that binds to the CASK kinase-like domain. As supported by biochemical and cellular studies, the interaction between liprin-alpha and CASK is unique to vertebrates, implying that the liprin-alpha/CASK interaction is likely to regulate higher-order brain functions in mammals. Consistently, we demonstrate that three recently identified X-linked mental retardation mutants of CASK are defective in binding to liprin-alpha. We also solved the liprin-alpha/liprin-beta SAM domain complex structure, which uncovers the mechanism underlying liprin heterodimerizaion. Finally, formation of the CASK/liprin-alpha/liprin-beta ternary complex suggests that liprins can mediate assembly of target proteins into large protein complexes capable of regulating numerous cellular activities. Liprin-mediated large signaling complex organization revealed by the liprin-alpha/CASK and liprin-alpha/liprin-beta complex structures.,Wei Z, Zheng S, Spangler SA, Yu C, Hoogenraad CC, Zhang M Mol Cell. 2011 Aug 19;43(4):586-98. PMID:21855798[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||||||
