4emo | pdb_00004emo
Crystal structure of the PH domain of SHARPIN
Structural highlights
FunctionSHRPN_HUMAN Component of the LUBAC complex which conjugates linear polyubiquitin chains in a head-to-tail manner to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation. LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B and the JNK signaling pathways. Linear ubiquitination mediated by the LUBAC complex interferes with TNF-induced cell death and thereby prevents inflammation. LUBAC is proposed to be recruited to the TNF-R1 signaling complex (TNF-RSC) following polyubiquitination of TNF-RSC components by BIRC2 and/or BIRC3 and to conjugate linear polyubiquitin to IKBKG and possibly other components contributing to the stability of the complex. Together with FAM105B/otulin, the LUBAC complex regulates the canonical Wnt signaling during angiogenesis.[1] [2] [3] Publication Abstract from PubMedE3 ubiquitin ligase complex called LUBAC (linear ubiquitin chain assembly complex) that catalyses the formation of linear ubiquitin chains and regulates immune and apoptopic signalling pathways. The C-terminal half of SHARPIN contains ubiquitin like domain (UBL) and Npl4-zinc finger (NZF) domains that mediate the interaction with the LUBAC subunit HOIP and ubiquitin, respectively. In contrast, the N-terminal region does not show any homology with known protein interaction domains but has been suggested to be responsible for self-association of SHARPIN, presumably via a coiled-coil region. We have determined the crystal structure of the N-terminal portion of SHARPIN, which adopts the highly conserved pleckstrin homology (PH) superfold that is often used as a scaffold to create protein interaction modules. We show that in SHARPIN this domain does not appear to be used as a ligand recognition domain since it lacks many of the surface properties that are present in other PH fold-based interaction modules. Instead it acts as a dimerization module extending the functional applications of this superfold. Structural analysis of SHARPIN, a subunit of a large multi-protein E3 ubiquitin ligase, reveals a novel dimerization function for the pleckstrin homology superfold.,Stieglitz B, Haire LF, Dikic I, Rittinger K J Biol Chem. 2012 May 1. PMID:22549881[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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