TRAP1

TRAP1 Full Name

TNF receptor-associated protein 1

TRAP1 Introduction

TRAP1 (TNF receptor-associated protein 1) is a mitochondrial homolog of the Hsp90 chaperone family that resides primarily in the inner mitochondrial membrane and matrix. The protein is constitutively expressed in many tissues but is markedly upregulated in tumors, where it supports the metabolic adaptations of cancer cells. TRAP1 bears an N-terminal mitochondrial targeting sequence and the characteristic Hsp90 ATPase domain, with client proteins that include SDHA, cyclophilin D, and several components of the electron transport chain.

Figure 1. The structure of TRAP1.

Mitochondrial Chaperone in Stress Adaptation
TRAP1 uses the energy of ATP hydrolysis to stabilize client proteins and to prevent their misfolding and aggregation under conditions of oxidative or metabolic stress. Among its clients, succinate dehydrogenase subunit A (SDHA) is chaperoned through assembly of complex II, while cyclophilin D is held in an inactive conformation that suppresses opening of the mitochondrial permeability transition pore. TRAP1 is also a client of PINK1 and is phosphorylated on serine 637 by PKA, both of which modulate its chaperone activity and its interactions with the mitochondrial respiratory chain.

Cancer Metabolism and Neurodegeneration
TRAP1 is overexpressed in many cancers, where it suppresses mitochondrial respiration, sustains ROS scavenging through an interaction with mitochondrial SOD2, and promotes resistance to apoptosis. Small-molecule TRAP1 inhibitors such as gamitrinib are being developed as anticancer agents because they selectively kill tumor cells with elevated mitochondrial chaperone activity. Loss-of-function TRAP1 variants have been associated with Parkinson disease and with cellular models of PINK1/Parkin-related neurodegeneration, suggesting that TRAP1 supports dopaminergic neuron survival by maintaining mitochondrial protein quality control.

Alternate Names for TRAP1

TRAP1; TNF receptor-associated protein 1; heat shock protein 75 kDa, mitochondrial; HSP75; HSP90L; HSP 75; TRAP-1; TNFR-associated protein 1; tumor necrosis factor type 1 receptor associated protein; tumor necrosis factor type 1 receptor-associated protein;