2mpc | pdb_00002mpc

Solution structure of the pyrin domain of human Pyrin

spinqualitylabelsall models 2mpc Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2mpc is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Solution NMR Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease MEFV_HUMAN Defects in MEFV are the cause of familial Mediterranean fever autosomal recessive (ARFMF) [MIM:249100. ARFMF is an inherited disorder characterized by recurrent episodic fever, serosal inflammation and pain in the abdomen, chest or joints. ARFMF is frequently complicated by amyloidosis, which leads to renal failure and can be prophylactically treated with colchicine. ARFMF primarily affects ancestral ethnic groups living around the Mediterranean basin: North African Jews, Armenians, Arabs and Turks. The disease is also distributed in other populations including Greeks, Cypriots, Italians and Spanish, although at a lower prevalence. Defects in MEFV are the cause of familial Mediterranean fever autosomal dominant (ADFMF) [MIM:134610. ADFMF is characterized by periodic fever, serosal inflammation and pain in the abdomen, chest or joints as seen also in the autosomal recessive form of the disease. It is associated with renal amyloidosis and characterized by colchicine unresponsiveness. Function MEFV_HUMAN Probably controls the inflammatory response in myelomonocytic cells at the level of the cytoskeleton organization. Publication Abstract from PubMed Inflammasomes are macromolecular complexes that mediate inflammatory and cell death responses to pathogens and cellular stress signals. Dysregulated inflammasome activation is associated with autoinflammatory syndromes and several common diseases. During inflammasome assembly, oligomerized cytosolic pattern recognition receptors recruit procaspase-1 and procaspase-8 via the adaptor protein ASC. Inflammasome assembly is mediated by pyrin domains (PYDs) and caspase recruitment domains, which are protein interaction domains of the death fold superfamily. However, the molecular details of their interactions are poorly understood. We have studied the interaction between ASC and pyrin PYDs that mediates ASC recruitment to the pyrin inflammasome, which is implicated in the pathogenesis of familial Mediterranean fever. We demonstrate that both the ASC and pyrin PYDs have multifaceted binding modes, involving three sites on pyrin PYD and two sites on ASC PYD. Molecular docking of pyrin-ASC PYD complexes showed that pyrin PYD can simultaneously interact with up to three ASC PYDs. Furthermore, ASC PYD can self-associate and interact with pyrin, consistent with previous reports that pyrin promotes ASC clustering to form a proinflammatory complex. Finally, the effects of familial Mediterranean fever-associated mutations, R42W and A89T, on structural and functional properties of pyrin PYD were investigated. The R42W mutation had a significant effect on structure and increased stability. Although the R42W mutant exhibited reduced interaction with ASC, it also bound less to the pyrin B-box domain responsible for autoinhibition and hence may be constitutively active. Our data give new insights into the binding modes of PYDs and inflammasome architecture. Identification of multifaceted binding modes for pyrin and ASC pyrin domains gives insights into pyrin inflammasome assembly.,Vajjhala PR, Kaiser S, Smith SJ, Ong QR, Soh SL, Stacey KJ, Hill JM J Biol Chem. 2014 Aug 22;289(34):23504-19. doi: 10.1074/jbc.M114.553305. Epub , 2014 Jul 8. PMID:25006247 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Pyrin domain

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