The Hsp90 cochaperone, FKBP51, increases Tau stability and polymerizes microtubules.
Imbalanced protein load within cells is a critical aspect for most diseases of aging. In particular, the accumulation of proteins into neurotoxic aggregates is a common thread for a host of neurodegenerative diseases. Our previous work demonstrated that age-related changes to the cellular chaperone repertoire contributes to abnormal buildup of the microtubule-associated protein tau that accumulates in a group of diseases termed tauopathies, the most common being Alzheimer's disease. Here, we show that the Hsp90 cochaperone, FK506-binding protein 51 (FKBP51), which possesses both an Hsp90-interacting tetratricopeptide domain and a peptidyl-prolyl cis-trans isomerase (PPIase) domain, prevents tau clearance and regulates its phosphorylation status. Regulation of the latter is dependent on the PPIase activity of FKBP51. FKB51 enhances the association of tau with Hsp90, but the FKBP51/tau interaction is not dependent on Hsp90. In vitro FKBP51 stabilizes microtubules with tau in a reaction depending on the PPIase activity of FKBP51. Based on these new findings, we propose that FKBP51 can use the Hsp90 complex to isomerize tau, altering its phosphorylation pattern and stabilizing microtubules.
Jinwal
Umesh K
UK
Johnnie B. Byrd Sr. Alzheimer's Research Institute and Department of Molecular Medicine, University of South Florida, Tampa, Florida 33613, USA.
Koren
John
J
Borysov
Sergiy I
SI
Schmid
Andreas B
AB
Abisambra
Jose F
JF
Blair
Laura J
LJ
Johnson
Amelia G
AG
Jones
Jeffrey R
JR
Shults
Cody L
CL
O'Leary
John C
JC
Jin
Ying
Y
Buchner
Johannes
J
Cox
Marc B
MB
Dickey
Chad A
CA
D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D002461:Cell Line, Transformed; D002918:Chymotrypsin / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009865:Oocytes; D019696:Peptidylprolyl Isomerase / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D014981:Xenopus; D016875:tau Proteins / Q000378:metabolism*; D000099159:Tacrolimus Binding Protein 5
D016227:Benzoquinones; D002918:Chymotrypsin; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D019696:Peptidylprolyl Isomerase; D034741:RNA, Small Interfering; D022021:Tacrolimus Binding Proteins; D016875:tau Proteins; D000099159:Tacrolimus Binding Protein 5; C112765:tanespimycin