title: Chaperone-like Activity of Calnuc Prevents Amyloid Aggregation.
abstract: Calnuc is a ubiquitously expressed protein of the EF-hand Ca2+-binding superfamily. Previous studies have implicated it in Ca2+-sensitive physiological processes, whereas details of its function and involvement in human diseases are lacking. Drawing upon the sequence homology of calnuc with calreticulin, we propose it functions as a molecular chaperone-like protein. In cells under thermal, chemical [urea and guanidinium chloride (GdmCl)], and acidic stress, calnuc exhibits properties similar to those of established chaperone-like proteins (GRP78, spectrin, and α-crystallin), effectively demonstrated by its ability to suppress aggregation of malate dehydrogenase (MDH), alcohol dehydrogenase, and catalase. Calnuc aids in refolding of MDH with retention of 80% of its enzymatic activity. In HEK293 cells subjected to heat shock, calnuc chaperones luciferase, protecting its activity. Our in vitro and cell culture results establish the ability of calnuc to inhibit fibrillation of insulin and lysozyme and validate its neuroprotective role in cells treated with amyloid fibrils. Calnuc also rescues cells from fibrillar toxicity (caused by misfolded or aggregated proteins), providing a plausible explanation for the previous observation of its low level of expression in brains affected by Alzheimer's disease. We propose that calnuc is possibly involved in controlling protein unfolding diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), prion disease, and type II diabetes.
authors.affiliation: Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras , Chennai 600 036, India.
authors.forename: Madhavi
authors.initials: M
authors.lastname: Kanuru
authors.affiliation: Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras , Chennai 600 036, India.
authors.forename: Gopala Krishna
authors.identifier: http://orcid.org/0000-0001-8232-3935
authors.initials: GK
authors.lastname: Aradhyam
mesh_terms: D000426:Alcohol Dehydrogenase / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism; D000682:Amyloid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002374:Catalase / Q000737:chemistry / Q000378:metabolism; D002942:Circular Dichroism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D057809:HEK293 Cells; D006358:Hot Temperature; D006801:Humans; D008291:Malate Dehydrogenase / Q000737:chemistry / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D000080866:Nucleobindins; D010300:Parkinson Disease / Q000378:metabolism; D017096:Prion Diseases / Q000378:metabolism; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological; D058849:Protein Refolding; D058767:Protein Unfolding
chemical_list: D000682:Amyloid; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D000080866:Nucleobindins; D066329:Protein Aggregates; D000426:Alcohol Dehydrogenase; D008291:Malate Dehydrogenase; D002374:Catalase