Neurodegenerative disorders include a large variety of conditions that include a progressive decay of neural function. Included in this group are hereditary spastic paraplegia (HSP) and mit-CHAP-60 which belong to a larger group of inherited conditions characterized by psychomotor developmental delay, involuntary eye movement (nystagmus), low muscle tone (hypotonia) and weakness, and prominent stiffness (spasticity) that may lead to impaired ability to walk. Both HSP and mit-CHAP-60 have been linked to respective point mutations in the HSPD1 gene that encodes the human heat shock protein 60 (hsp60), an essential protein complex that assists in protein folding termed a chaperonin. The main goal of the proposed research project is to identify and characterize structural changes that result from the point mutations that lead to these two diseases. To date, there has not been a structure deposited in the PDB databank for the human heat shock protein 60 (also called CPN 60 and hsp60). Therefore, we do not have a detailed understanding for the decreased activity of hsp60 that leads to the development of these diseases. Our working hypothesis is that the protein folding pathway of the hsp60/10 chaperonin system is altered by the each point mutation through a destabilization of the 14 subunit complex that in turn lowers overall chaperonin activity. Chaperonin activity in general is critical to all living cells where aloss in said activity is lethal. These defective chaperonin diseases result in a condition where the chaperonin is still slightly active but not sufficiently active to allow for a normal phenotype. Th overarching goal of the proposed project is to define the molecular basis for hereditary spastic paraplegia and Mit-CHAP- 60 disease.

Public Health Relevance

Almost every function in a cell is the result of the action of proteins and so it is critical that proteins fold properly through the use of specialized protein complexes called chaperonins. Our research investigates the process by which human chaperonins fold misfolded proteins by probing the changes in the chaperonin that take place during a protein folding cycle. Understanding how protein folding intermediates function might then lead to targets for the treatment of diseases such as hereditary spastic paraplegia and mitochondrial hsp60 chaperonopathy.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Continuance Award (SC3)
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Special Emphasis Panel (ZGM1-TWD-3 (SC))
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Krasnewich, Donna M
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University of Texas El Paso
Schools of Arts and Sciences
El Paso
United States
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Bhatt, Jay M; Enriquez, Adrian S; Wang, Jinliang et al. (2018) Single-Ring Intermediates Are Essential for Some Chaperonins. Front Mol Biosci 5:42
Enriquez, Adrian S; Rojo, Humberto M; Bhatt, Jay M et al. (2017) The human mitochondrial Hsp60 in the APO conformation forms a stable tetradecameric complex. Cell Cycle 16:1309-1319
Calton, Christine M; Bronnimann, Matthew P; Manson, Ariana R et al. (2017) Translocation of the papillomavirus L2/vDNA complex across the limiting membrane requires the onset of mitosis. PLoS Pathog 13:e1006200
Molugu, Sudheer K; Hildenbrand, Zacariah L; Morgan, David Gene et al. (2016) Ring Separation Highlights the Protein-Folding Mechanism Used by the Phage EL-Encoded Chaperonin. Structure 24:537-546