XIAP Is a copper binding protein deregulated in Wilson's disease and other copper toxicosis disorders.
X-linked inhibitor of apoptosis (XIAP), known primarily for its caspase inhibitory properties, has recently been shown to interact with and regulate the levels of COMMD1, a protein associated with a form of canine copper toxicosis. Here, we describe a role for XIAP in copper metabolism. We find that XIAP levels are greatly reduced by intracellular copper accumulation in Wilson's disease and other copper toxicosis disorders and in cells cultured under high copper conditions. Elevated copper levels result in a profound, reversible conformational change in XIAP due to the direct binding of copper to XIAP, which accelerates its degradation and significantly decreases its ability to inhibit caspase-3. This results in a lowering of the apoptotic threshold, sensitizing the cell to apoptosis. These data provide an unsuspected link between copper homeostasis and the regulation of cell death through XIAP and may contribute to the pathophysiology of copper toxicosis disorders.
Department of Pathology, University of Michigan Medical School, Ann Arbor, 48109, USA.
Arjmand R
AR
Mufti
Ezra
E
Burstein
Rebecca A
RA
Csomos
Paul C F
PC
Graf
John C
JC
Wilkinson
Robert D
RD
Dick
Madhavi
M
Challa
Jae-Kyoung
JK
Son
Shawn B
SB
Bratton
Grace L
GL
Su
George J
GJ
Brewer
Ursula
U
Jakob
Colin S
CS
Duckett
D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000502:physiology; D002460:Cell Line; D003300:Copper / Q000506:poisoning*; D024202:Electrophoretic Mobility Shift Assay; D006527:Hepatolenticular Degeneration / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008954:Models, Biological; D011487:Protein Conformation; D015398:Signal Transduction; D014162:Transfection; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology
D002352:Carrier Proteins; D051034:Inhibitor of Apoptosis Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C023548:copper-binding protein; D003300:Copper; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases