Valosine-containing protein (VCP) (VCP)

Valosine-containing protein (VCP), also known as p97, is a highly conserved AAA+ ATPase that functions as a central hub in the cellular protein quality control network (UniProt P55072; Meyer et al., 2012). It is composed of an N-terminal domain and two tandem ATPase domains, D1 and D2, which form a hexameric ring structure; the D2 domain is the primary site of ATP hydrolysis and provides the mechanical force required for its chaperone activities (Tang & Xia, 2016). VCP facilitates the extraction of ubiquitinated proteins from membranes or macromolecular complexes, directing them toward degradation via the proteasome or autophagy pathways, a process essential for endoplasmic reticulum-associated degradation (ERAD) (Bastola et al., 2022). In cancer, VCP is frequently upregulated to cope with increased proteotoxic stress, and its inhibition leads to the accumulation of misfolded proteins, activation of the unfolded protein response (UPR), and subsequent apoptosis (Anderson et al., 2015). Mutations in VCP are linked to multisystem proteinopathy (MSP) and neurodegenerative conditions like amyotrophic lateral sclerosis (ALS), where impaired protein clearance leads to toxic aggregates (Tang & Xia, 2016). Small-molecule inhibitors such as CB-5083 specifically target the D2 ATPase domain to disrupt these vital functions, though clinical development has been hampered by side effects like reversible ocular toxicity (Anderson et al., 2015; Bastola et al., 2022).

Other names

p97Transitional endoplasmic reticulum ATPaseTERACDC48ATPase domain D2IBMPFDALS14

Competitive or allosteric inhibition of the D2 ATPase domain, which prevents the mechanical unfolding and extraction of ubiquitinated substrates, leading to lethal proteotoxic stress and apoptosis.