Mutations in the Human AAA+ Chaperone p97 and Related Diseases

Abstract

A number of neurodegenerative diseases have been linked to mutations in the human protein p97, an abundant cytosolic AAA+ (ATPase associated with various cellular activities) ATPase, that functions in a large number of cellular pathways. With the assistance of a variety of cofactors and adaptor proteins, p97 couples the energy of ATP hydrolysis to conformational changes that are necessary for its function. Disease-linked mutations, which are found at the interface between two main domains of p97, have been shown to alter the function of the protein, although the pathogenic mutations do not appear to alter the structure of individual subunit of p97 or the formation of the hexameric biological unit. While exactly how pathogenic mutations alter the cellular function of p97 remains unknown, functional, biochemical and structural differences between wild-type and pathogenic mutants of p97 are being identified. Here, we summarize recent progress in the study of p97 pathogenic mutants.

Valosin-containing protein VCP/p97 is essential for the intracellular development of Leishmania and its survival under heat stress

“…Our results emphasise the crucial role Li VCP plays in the parasite intracellular development and its survival particularly under heat stress. VCP is central to multiple essential protein quality control pathways and VCP‐associated mutations in humans have been implicated in a multitude of diseases, including cancer and neurodegeneration (Fessart et al, ; Meyer & Weihl, ; Tang & Xia, ). Thus, VCP/p97 has emerged as an important therapeutic target not only for cancer and neurodegeneration (Anderson et al, ; Chapman, Maksim, de la Cruz, & Clair, ; Vekaria, Home, Weir, Schoenen, & Rao, ) but also for parasitic diseases (Harbut et al, ).…”

“…VCP/p97 is indeed involved in the extraction of ubiquitylated proteins from the endoplasmic reticulum associated protein degradation (ERAD; Qi, Tsai, & Arvan, ; Wolf & Stolz, ) and similarly in the translocation of damaged mitochondrial proteins from the outer mitochondrial membrane into the cytosol (associated degradation; (Heo et al, ; Taylor & Rutter, ), the ribosome quality control (Brandman et al, ), the removal of chromatin‐bound proteins (Franz, Ackermann, & Hoppe, ), genome stability (Vaz, Halder, & Ramadan, ), stress granules clearance (Buchan, Kolaitis, Taylor, & Parker, ), and the removal of damaged lysosomes by autophagy (Papadopoulos et al, ). Consistent with its central role in essential protein quality control pathways, mutations in human VCP/p97 have been linked to several diseases, including cancer and neurodegenerative and muscular disorders (Fessart, Marza, Taouji, Delom, & Chevet, ; Meyer & Weihl, ; Tang & Xia, ).…”

Ubiquitin- and ATP-dependent unfoldase activity of P97/VCP•NPLOC4•UFD1L1 is enhanced by a mutation that causes multisystem proteinopathy

“…A significant incentive to gaining a deeper understanding of p97 mechanism of action is the deep connection between this protein and human disease, and possibly cancer therapy. Human p97 is mutated in the inherited, autosomal-dominant multisystem proteinopathy known as IBMPFD (53, 54). In addition, a small fraction of patients with inherited Amyotrophic Lateral Sclerosis (ALS/Lou Gehrig’s Disease) also carry mutations in p97 that overlap with those seen in IBMPFD patients (54, 55).…”

“…Human p97 is mutated in the inherited, autosomal-dominant multisystem proteinopathy known as IBMPFD (53, 54). In addition, a small fraction of patients with inherited Amyotrophic Lateral Sclerosis (ALS/Lou Gehrig’s Disease) also carry mutations in p97 that overlap with those seen in IBMPFD patients (54, 55). However, the mechanism of pathogenesis is not understood in either case.…”

A molecular switch for Cdc48 activity and localization during oxidative stress and aging

“…Multifunctionality of Cdc48 is encoded in its structurally flexible and highly conserved Nterminal domain, which contains the nuclear import domain 28 and also serves as anchor domain for multiple interactions with co-factors. Therefore, it is not surprising that the overwhelming majority of VCP mutations associated with diseases are on highly conserved residues (conserved also in yeast Cdc48) and most are located in the Nterminal domain 61,62 . Moreover, canonic mutations known to cause pathogenic disorders such as Paget's disease of bone, frontotemporal dementia (IBMPFD) and ALS have been identified as disrupting VCP nuclear localization 63 .…”