7l5x
From Proteopedia
p97-R155H mutant dodecamer II
Structural highlights
Disease[TERA_HUMAN] Defects in VCP are the cause of inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD) [MIM:167320]; also known as muscular dystrophy, limb-girdle, with Paget disease of bone or pagetoid amyotrophic lateral sclerosis or pagetoid neuroskeletal syndrome or lower motor neuron degeneration with Paget-like bone disease. IBMPFD features adult-onset proximal and distal muscle weakness (clinically resembling limb girdle muscular dystrophy), early-onset Paget disease of bone in most cases and premature frontotemporal dementia.[1] [2] [3] [4] [5] Defects in VCP are the cause of amyotrophic lateral sclerosis type 14 with or without frontotemporal dementia (ALS14) [MIM:613954]. ALS14 is a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. Patients with ALS14 may develop frontotemporal dementia.[6] Function[TERA_HUMAN] Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis. Involved in the formation of the transitional endoplasmic reticulum (tER). The transfer of membranes from the endoplasmic reticulum to the Golgi apparatus occurs via 50-70 nm transition vesicles which derive from part-rough, part-smooth transitional elements of the endoplasmic reticulum (tER). Vesicle budding from the tER is an ATP-dependent process. The ternary complex containing UFD1L, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome. The NPLOC4-UFD1L-VCP complex regulates spindle disassembly at the end of mitosis and is necessary for the formation of a closed nuclear envelope. Regulates E3 ubiquitin-protein ligase activity of RNF19A (By similarity). Component of the VCP/p97-AMFR/gp78 complex that participates in the final step of the sterol-mediated ubiquitination and endoplasmic reticulum-associated degradation (ERAD) of HMGCR. Also involved in DNA damage response: recruited to double-strand breaks (DSBs) sites in a RNF8- and RNF168-dependent manner and promotes the recruitment of TP53BP1 at DNA damage sites. Recruited to stalled replication forks by SPRTN: may act by mediating extraction of DNA polymerase eta (POLH) to prevent excessive translesion DNA synthesis and limit the incidence of mutations induced by DNA damage.[7] [8] [9] [10] [11] [12] [13] Publication Abstract from PubMedIBMPFD/ALS is a genetic disorder caused by a single amino acid mutation on the p97 ATPase, promoting ATPase activity and cofactor dysregulation. The disease mechanism underlying p97 ATPase malfunction remains unclear. To understand how the mutation alters the ATPase regulation, we assembled a full-length p97(R155H) with its p47 cofactor and first visualized their structures using single-particle cryo-EM. More than one-third of the population was the dodecameric form. Nucleotide presence dissociates the dodecamer into two hexamers for its highly elevated function. The N-domains of the p97(R155H) mutant all show up configurations in ADP- or ATPgammaS-bound states. Our functional and structural analyses showed that the p47 binding is likely to impact the p97(R155H) ATPase activities via changing the conformations of arginine fingers. These functional and structural analyses underline the ATPase dysregulation with the miscommunication between the functional modules of the p97(R155H). Structural and Functional Analysis of Disease-Linked p97 ATPase Mutant Complexes.,Nandi P, Li S, Columbres RCA, Wang F, Williams DR, Poh YP, Chou TF, Chiu PL Int J Mol Sci. 2021 Jul 28;22(15). pii: ijms22158079. doi: 10.3390/ijms22158079. PMID:34360842[14] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Large Structures | Vesicle-fusing ATPase | Chiu, P L | Chou, T F | Coulmbres, R C.A | Li, S | Malyutin, A G | Nandi, P | Poh, Y P | Wang, F | Williams, D R | Aaa+ atpase | Hydrolase | Motor protein
