Mechanism of Amyloidogenesis of a Bacterial AAA+ Chaperone.
Amyloids are fibrillar protein superstructures that are commonly associated with diseases in humans and with physiological functions in various organisms. The precise mechanisms of amyloid formation remain to be elucidated. Surprisingly, we discovered that a bacterial Escherichia coli chaperone-like ATPase, regulatory ATPase variant A (RavA), and specifically the LARA domain in RavA, forms amyloids under acidic conditions at elevated temperatures. RavA is involved in modulating the proper assembly of membrane respiratory complexes. LARA contains an N-terminal loop region followed by a β-sandwich-like folded core. Several approaches, including nuclear magnetic resonance spectroscopy and molecular dynamics simulations, were used to determine the mechanism by which LARA switches to an amyloid state. These studies revealed that the folded core of LARA is amyloidogenic and is protected by its N-terminal loop. At low pH and high temperatures, the interaction of the N-terminal loop with the folded core is disrupted, leading to amyloid formation.
Department of Biochemistry, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, ON M5S 1A8, Canada.
Sze Wah Samuel
SW
Chan
Department of Biochemistry, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, ON M5S 1A8, Canada; Molecular Structure and Function Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Jason
J
Yau
Department of Biochemistry, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, ON M5S 1A8, Canada; Molecular Structure and Function Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Christopher
C
Ing
Department of Biochemistry, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, ON M5S 1A8, Canada.
Kaiyin
K
Liu
Molecular Structure and Function Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Patrick
P
Farber
Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3E1, Canada.
Amy
A
Won
Department of Biochemistry, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, ON M5S 1A8, Canada.
Vaibhav
V
Bhandari
Department of Biochemistry, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, ON M5S 1A8, Canada.
Nareg
N
Kara-Yacoubian
Department of Biochemistry, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, ON M5S 1A8, Canada.
Thiago V
TV
Seraphim
Molecular Structure and Function Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Nilmadhab
N
Chakrabarti
Department of Biochemistry, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, ON M5S 1A8, Canada; Molecular Structure and Function Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Lewis E
LE
Kay
Department of Biochemistry, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, ON M5S 1A8, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3E1, Canada.
Christopher M
CM
Yip
Department of Biochemistry, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, ON M5S 1A8, Canada; Molecular Structure and Function Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Régis
R
Pomès
Department of Biochemistry, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, ON M5S 1A8, Canada; Molecular Structure and Function Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada. Electronic address: ssharpe@sickkids.ca.
Simon
S
Sharpe
Department of Biochemistry, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, ON M5S 1A8, Canada. Electronic address: walid.houry@utoronto.ca.
Walid A
WA
Houry
D000251:Adenosine Triphosphatases / Q000737:chemistry*; D020816:Amino Acid Motifs; D000682:Amyloid / Q000737:chemistry*; D029968:Escherichia coli Proteins / Q000737:chemistry*; D066329:Protein Aggregates; D000072417:Protein Domains
D000682:Amyloid; D029968:Escherichia coli Proteins; D066329:Protein Aggregates; D000251:Adenosine Triphosphatases; C508688:RavA protein, E coli