The Parkin co-regulated gene protein (PACRG) binds at the inner junction between doublet microtubules of the axoneme, a structure found in flagella and cilia. PACRG binds to the adaptor protein meiosis expressed gene 1 (MEIG1), but how they bind to microtubules is unknown. Here, we report the crystal structure of human PACRG in complex with MEIG1. PACRG adopts a helical repeat fold with a loop that interacts with MEIG1. Using the structure of the axonemal doublet microtubule from the protozoan Chlamydomonas reinhardtii and single-molecule fluorescence microscopy, we propose that PACRG binds to microtubules while simultaneously recruiting free tubulin to catalyze formation of the inner junction. We show that the homologous PACRG-like protein also mediates dual tubulin interactions but does not bind MEIG1. Our findings establish a framework to assess the function of the PACRG family of proteins and MEIG1 in regulating axoneme assembly.
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http://dx.doi.org/10.1016/j.str.2021.01.001 | DOI Listing |
The interaction between meiosis-expressed gene 1 (MEIG1) and Parkin co-regulated gene (PACRG) is a critical determinant of spermiogenesis, the process by which round spermatids mature into functional spermatozoa. Disruption of the MEIG1-PACRG complex can impair sperm development, highlighting its potential as a therapeutic target for addressing male infertility or for the development of non-hormonal contraceptive methods. This study used virtual screening, molecular docking, and molecular dynamics (MD) simulations to identify small molecule inhibitors targeting the MEIG1-PACRG interface.
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April 2023
Department of Physics and Astronomy, Wayne State University, Detroit, Michigan, USA.
Interactions between the meiosis-expressed gene 1 (MEIG1) and Parkin co-regulated gene (PACRG) protein are critical in the formation of mature sperm cells. Targeting either MEIG1 or PACRG protein could be a contraceptive strategy. The W50A and Y68A mutations on MEIG1 are known to interrupt the MEIG1-PACRG interactions resulting in defective sperm cells.
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September 2021
Division of Animal Science, University of Missouri, Columbia, MO 65211, USA.
Propagation of paternal sperm-contributed mitochondrial genes, resulting in heteroplasmy, is seldom observed in mammals due to post-fertilization degradation of sperm mitochondria, referred to as sperm mitophagy. Whole organelle sperm mitochondrion degradation is thought to be mediated by the interplay between the ubiquitin-proteasome system (UPS) and the autophagic pathway (Song et al., Proc.
View Article and Find Full Text PDFMolecules
April 2021
School of Life Sciences, Zhaoqing University, Zhaoqing 526061, China.
( co-regulated gene) shares a bi-directional promoter with the Parkinson's disease-associated gene , but the physiological roles of PACRG have not yet been fully elucidated. Recombinant expression methods are indispensable for protein structural and functional studies. In this study, the coding region of was cloned to a conventional vector pQE80L, as well as two cold-shock vectors pCold II and pCold-GST, respectively.
View Article and Find Full Text PDFStructure
June 2021
Department of Pharmacology & Therapeutics, McGill University, Montreal, QC, Canada; Centre de Recherche en Biologie Structurale - FRQS, McGill University, Montreal, QC, Canada. Electronic address:
The Parkin co-regulated gene protein (PACRG) binds at the inner junction between doublet microtubules of the axoneme, a structure found in flagella and cilia. PACRG binds to the adaptor protein meiosis expressed gene 1 (MEIG1), but how they bind to microtubules is unknown. Here, we report the crystal structure of human PACRG in complex with MEIG1.
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