Mitochondrial ClpX activates an essential biosynthetic enzyme through partial unfolding

Author:

Kardon Julia R123ORCID,Moroco Jamie A4ORCID,Engen John R4ORCID,Baker Tania A23ORCID

Affiliation:

1. Department of Biochemistry, Brandeis University, Waltham, United States

2. Department of Biology, Massachusetts Institute of Technology, Cambridge, United States

3. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, United States

4. Department of Chemistry and Chemical Biology, Northeastern University, Boston, United States

Abstract

Mitochondria control the activity, quality, and lifetime of their proteins with an autonomous system of chaperones, but the signals that direct substrate-chaperone interactions and outcomes are poorly understood. We previously discovered that the mitochondrial AAA+ protein unfoldase ClpX (mtClpX) activates the initiating enzyme for heme biosynthesis, 5-aminolevulinic acid synthase (ALAS), by promoting cofactor incorporation. Here, we ask how mtClpX accomplishes this activation. Using S. cerevisiae proteins, we identified sequence and structural features within ALAS that position mtClpX and provide it with a grip for acting on ALAS. Observation of ALAS undergoing remodeling by mtClpX revealed that unfolding is limited to a region extending from the mtClpX-binding site to the active site. Unfolding along this path is required for mtClpX to gate cofactor binding to ALAS. This targeted unfolding contrasts with the global unfolding canonically executed by ClpX homologs and provides insight into how substrate-chaperone interactions direct the outcome of remodeling.

Funder

National Institute of Diabetes and Digestive and Kidney Diseases

Howard Hughes Medical Institute

National Institute of General Medical Sciences

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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