title: Structural analysis of SHARPIN, a subunit of a large multi-protein E3 ubiquitin ligase, reveals a novel dimerization function for the pleckstrin homology superfold.
abstract: SHARPIN (SHANK-associated RH domain interacting protein) is part of a large multi-protein E3 ubiquitin ligase complex called LUBAC (linear ubiquitin chain assembly complex), which catalyzes the formation of linear ubiquitin chains and regulates immune and apoptopic signaling pathways. The C-terminal half of SHARPIN contains ubiquitin-like domain and Npl4-zinc finger 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 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 because it lacks many of the surface properties that are present in other pleckstrin homology fold-based interaction modules. Instead, it acts as a dimerization module extending the functional applications of this superfold.
authors.affiliation: Division of Molecular Structure, Medical Research Council National Institute for Medical Research, The Ridgeway, London NW7 1AA, United Kingdom.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Stieglitz
authors.forename: Lesley F
authors.initials: LF
authors.lastname: Haire
authors.forename: Ivan
authors.initials: I
authors.lastname: Dikic
authors.forename: Katrin
authors.initials: K
authors.lastname: Rittinger
mesh_terms: D001798:Blood Proteins / Q000737:chemistry; D018360:Crystallography, X-Ray; D006801:Humans; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D010750:Phosphoproteins / Q000737:chemistry; D017510:Protein Folding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry*; D013329:Structure-Activity Relationship; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry*; D016335:Zinc Fingers
chemical_list: D001798:Blood Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D021122:Protein Subunits; C039077:platelet protein P47; C425287:sharpin; D044767:Ubiquitin-Protein Ligases