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Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP

journal contribution
posted on 10.12.2020, 22:00 by Philip R Strack, Erica J Brodie, Hanmiao Zhan, VJ Schuenemann, Liz J Valente, Tamanna Saiyed, Bradley R Lowth, LM Angley, Matthew Perugini, K Zeth, Kaye Truscott, David Dougan
Over a decade ago Polymerase δ interacting protein of 38 kDa (PDIP38) was proposed to play a role in DNA repair. Since this time, both the physiological function and subcellular location of PDIP38 has remained ambiguous and our present understanding of PDIP38 function has been hampered by a lack of detailed biochemical and structural studies. Here we show, that human PDIP38 is directed to the mitochondrion in a membrane potential dependent manner, where it resides in the matrix compartment, together with its partner protein CLPX. Our structural analysis revealed that PDIP38 is composed of two conserved domains separated by an α/β linker region. The N-terminal (YccV-like) domain of PDIP38 forms an SH3-like β-barrel, which interacts specifically with CLPX, via the adaptor docking loop within the N-terminal Zinc binding domain of CLPX. In contrast, the C-terminal (DUF525) domain forms an immunoglobin-like β-sandwich fold, which contains a highly conserved putative substrate binding pocket. Importantly, PDIP38 modulates the substrate specificity of CLPX and protects CLPX from LONM-mediated degradation, which stabilises the cellular levels of CLPX. Collectively, our findings shed new light on the mechanism and function of mitochondrial PDIP38, demonstrating that PDIP38 is a bona fide adaptor protein for the mitochondrial protease, CLPXP.

Funding

This work was supported by an Australian Research Council (ARC) Discovery Project (DP0770013) to D.A.D. and K.N.T., and ARC Future Fellowship to K.N.T. (FT0992033) and an ARC Australian Research Fellowship to D.A.D. (DP110103936). P.R.S. and H.Z. were supported by a La Trobe University Postgraduate Award, E.J.B. and B.R.L. were supported by Australian Postgraduate Awards and T.S. was supported by a Cooperative Research Centre postgraduate award. We thank Dr. Clemens Vonrhein from the Buster development group for his help with handling of the crystallographic data and M. Miasari for cloning of PDIP38N and PDIP38C into pGEX-4T.

History

School

  • School of Molecular Sciences

Publication Date

06/11/2020

Journal

Communications Biology

Volume

3

Issue

1

Article Number

646

Pagination

12p. (p. 1-12)

Publisher

Springer Nature

ISSN

2399-3642

Rights Statement

The Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.