Valosin-Containing Protein is a protein encoded by the [VCP](/genes/vcp) gene. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.
Valosin-Containing Protein is a protein encoded by the [VCP](/genes/vcp) gene. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.
Valosin-Containing Protein (VCP) (also known as p97) is a hexameric AAA+ ATPase critical for protein degradation, DNA repair, and membrane fusion. VCP mutations cause inclusion body myopathy with early-onset Paget disease of bone (PDB) and frontotemporal dementia (IBMPFD), now termed multisystem proteinopathy (MSP).
Gene Overview
Structure
VCP forms a homohexameric complex:
N-terminal Domain - Substrate binding and cofactor interactions
ATPase Domain (D1 and D2) - Hexameric ring with ATPase activity
C-terminal Domain - Regulatory interactions
Cofactors
UFD1L - Ubiquitin recognition
NPL4 - Substrate delivery
p47 - Membrane trafficking
UBXD7/8 - Autophagy regulation
Pathogenic Mechanisms
Protein Quality Control
VCP is central to ubiquitin-proteasome system (UPS) function:
Extracts ubiquitinated proteins from complexes
Delivers substrates to proteasome
Mutations impair protein clearance
Accumulation of toxic protein aggregates
Autophagy
VCP mutations disrupt autophagy:
Impaired autophagosome-lysosome fusion
Defective mitophagy (mitochondrial clearance)
Disrupted ribophagy (ribosome clearance)
Accumulation of damaged organelles
DNA Repair
VCP participates in DNA damage response:
Double-strand break repair
Replication stress response
Chromatin remodeling
Genomic instability in disease
Membrane Trafficking
Essential for membrane fusion events:
Golgi reassembly
ER network maintenance
Endosomal trafficking
Nuclear envelope reformation
Disease Associations
Multisystem Proteinopathy (MSP)
VCP mutations cause a triad of disorders:
Inclusion Body Myopathy - Progressive muscle weakness, typically starting in adulthood
Paget Disease of Bone - Increased bone turnover, bone pain, deformities