Abstract：
:The accumulation of protein damage in aging organisms is thought to contribute to many aging-related diseases. Yet the properties determining which proteins are most susceptible remain poorly understood. Are certain conformations more vulnerable? Which chaperones are the main guardians? We address these questions with a system-wide model of E. coli proteostasis. By predicting how proteins with different folding properties respond to each chaperone's concentration, the model computes "damage fingerprints" that identify unfolded conformations as the major damage target. What matters most is not a protein's stability or difficulty of folding, but its dwell time in an unfolded state. The main guardian chaperone is DnaK because its client proteins spend more time unfolded than clients of GroEL, providing a mechanism for why the cell's capacity to handle stress is more sensitive to DnaK levels. Also, we find that chaperones are protectors, not recyclers. This model describes how cells resist stress and indicates that designing chaperone-targeting drugs may require whole-cell, system-wide modeling.
journal_name
Cell Systjournal_title
Cell systemsauthors
Santra M,Dill KA,de Graff AMRdoi
10.1016/j.cels.2018.05.001subject
Has Abstractpub_date
2018-06-27 00:00:00pages
743-751.e3issue
6eissn
2405-4712issn
2405-4720pii
S2405-4712(18)30189-3journal_volume
6pub_type
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