Huntingtin has a membrane association signal that can modulate huntingtin aggregation, nuclear entry and toxicity.
Huntington's disease is caused by an expanded polyglutamine tract in huntingtin protein, leading to accumulation of huntingtin in the nuclei of striatal neurons. The 18 amino-acid amino-terminus of huntingtin is an amphipathic alpha helical membrane-binding domain that can reversibly target to vesicles and the endoplasmic reticulum (ER). The association of huntingtin to the ER is affected by ER stress. A single point mutation in huntingtin 1-18 predicted to disrupt this helical structure displayed striking phenotypes of complete inhibition of polyglutamine-mediated aggregation, increased huntingtin nuclear accumulation and greatly increased mutant huntingtin toxicity in a striatal-derived mouse cell line. Huntingtin vesicular interaction mediated by 1-18 is specific to late endosomes and autophagic vesicles. We propose that huntingtin has a normal biological function as an ER-associated protein that can translocate to the nucleus and back out in response to ER stress or other events. The increased nuclear entry of mutant huntingtin due to loss of ER-targeting results in increased toxicity.
Atwal
Randy Singh
RS
Department of Biochemistry and Biomedical Sciences, McMaster University, HSC 4H24A, 1200 Main Street West, Hamilton, Ontario, Canada.
Xia
Jianrun
J
Pinchev
Deborah
D
Taylor
Jillian
J
Epand
Richard M
RM
Truant
Ray
R
D000595:Amino Acid Sequence; D000818:Animals; D001343:Autophagy; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism*; D017124:Conserved Sequence; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism; D011992:Endosomes / Q000737:chemistry / Q000378:metabolism; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins