# CLPP

## Overview
The CLPP gene encodes the caseinolytic mitochondrial matrix peptidase proteolytic subunit, a crucial component of the mitochondrial protease complex involved in protein quality control within the mitochondria. This protease is categorized as a serine protease and is integral to the ATP-dependent ClpXP complex, where it collaborates with the chaperone CLPX to degrade misfolded or damaged proteins, thereby maintaining mitochondrial protein homeostasis (Jenkinson2013Perrault; Nouri2020Mitochondrial). The CLPP protein forms a heptameric ring structure that assembles into a tetradecamer, creating a proteolytic chamber essential for its function (Kang2004Crystallography; Kang2005Human). Mutations in the CLPP gene are linked to Perrault syndrome, a disorder characterized by sensorineural hearing loss and ovarian dysgenesis, underscoring the gene's clinical significance (Brodie2018Perrault; Jenkinson2013Perrault). Additionally, CLPP is implicated in various cellular processes, including the regulation of mitochondrial quality control and the mitochondrial unfolded protein response, highlighting its broader role in cellular metabolism and disease (Deepa2016Downregulation; Wang2018Mitochondrial).

## Structure
The human CLPP protein is a mitochondrial matrix protease that forms a heptameric ring structure, which assembles into a tetradecamer when two heptameric rings join face-to-face. This assembly creates an aqueous chamber containing the proteolytic active sites, accessible through axial channels (Kang2004Crystallography; Kang2005Human). Each CLPP monomer is wedge-shaped, featuring a globular domain with a 28-Å long α/β arm, and contains two perpendicular β sheets (Kang2004Crystallography). The N-terminal region of CLPP is crucial for its function, forming part of the axial channel that influences substrate passage (Kang2004Crystallography).

The protein's structure is characterized by its axial channel, hydrophobic lateral surface, and flexible C-terminal region, which play roles in its function and interactions (Kang2004Crystallography). The CLPP protein is similar to its bacterial counterpart, with a root mean square deviation of 0.63 Å for the Ca backbone of residues 18-190, indicating a high degree of structural conservation (Kang2004Crystallography). The C-terminal domain, unique to mammalian CLPP proteins, affects heptamer assembly and stability (Kang2004Crystallography).

## Function
The CLPP gene encodes a mitochondrial protease known as caseinolytic peptidase P, which plays a crucial role in maintaining mitochondrial protein homeostasis by degrading misfolded or damaged proteins within the mitochondrial matrix. This protease is part of the ATP-dependent ClpXP complex, where it works in conjunction with the chaperone CLPX to facilitate protein unfolding and translocation (Jenkinson2013Perrault; Nouri2020Mitochondrial). The active form of CLPP is a barrel-shaped tetradecamer, formed by the association of two heptameric rings, creating a central cavity for proteolysis (Jenkinson2013Perrault).

CLPP is involved in several critical cellular processes, including the regulation of the mitochondrial unfolded protein response (UPRmt), which is essential for maintaining mitochondrial integrity and function (Deepa2016Downregulation; Wang2018Mitochondrial). It also plays a role in the degradation of mitochondrial PTEN-induced kinase 1 (PINK1), which is important for regulating mitochondrial quality control and is associated with neurodegenerative diseases like Parkinson's disease (Luo2021Human). The protease is active in various tissues, with high expression in skeletal muscle and moderate expression in the heart, liver, and pancreas (Luo2021Human).

## Clinical Significance
Mutations in the CLPP gene are associated with Perrault syndrome, a rare autosomal-recessive disorder characterized by sensorineural hearing loss and ovarian dysgenesis. In females, this condition often leads to primary ovarian failure, while both genders can experience sensorineural hearing loss. Additional symptoms may include ataxia, intellectual disability, and other neurological impairments (Brodie2018Perrault; Jenkinson2013Perrault). Specific mutations, such as missense mutations and frameshift deletions, have been identified in various families, leading to diverse clinical presentations (Theunissen2016Specific; Ahmed2015Exome).

The CLPP gene encodes a mitochondrial protease that is crucial for maintaining mitochondrial protein homeostasis. Mutations can disrupt the protease's function, leading to mitochondrial dysfunction and the accumulation of mitochondrial DNA and proteins, which are linked to the symptoms observed in Perrault syndrome (Theunissen2016Specific; Gispert2013Loss). In addition to Perrault syndrome, altered expression of CLPP has been implicated in metabolic disorders, such as impaired thermogenesis and resistance to diet-induced obesity, highlighting its broader role in cellular metabolism (Becker2018CLPP). Understanding these mutations and their effects on mitochondrial function is crucial for developing potential therapeutic strategies.

## Interactions
The human gene CLPP encodes a mitochondrial matrix protease that forms a complex with the ATP-dependent chaperone CLPX. This interaction is crucial for the degradation of misfolded or damaged proteins within the mitochondria. CLPP typically exists as a heptamer, which can assemble into a tetradecamer in the presence of CLPX and ATP, forming a complex with two CLPX hexamers. This assembly is essential for its proteolytic activity, as it stabilizes the active conformation of CLPP and facilitates substrate processing (Kang2005Human).

The interaction between CLPP and CLPX involves both static high-affinity contacts and dynamic interactions. The static contacts occur between the IGF loops of CLPX and hydrophobic pockets on the apical surface of each CLPP heptameric ring. Dynamic interactions involve the N-terminal region of CLPP interacting with the axial pore-2 loops of CLPX, which vary with the nucleotide state of the ATPase protomers (Alexopoulos2012ClpP:).

CLPP's interaction with CLPX is transient and weak, but CLPX exerts an allosteric effect to stabilize the tetradecamer form of CLPP, enhancing its peptidase activity. This interaction is crucial for regulating the degradation of specific proteins during ATP-dependent proteolytic cycles (Kang2005Human).


## References


[1. (Luo2021Human) Baozhu Luo, Yu Ma, YuanZheng Zhou, Nannan Zhang, and Youfu Luo. Human clpp protease, a promising therapy target for diseases of mitochondrial dysfunction. Drug Discovery Today, 26(4):968–981, April 2021. URL: http://dx.doi.org/10.1016/j.drudis.2021.01.007, doi:10.1016/j.drudis.2021.01.007. This article has 22 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.drudis.2021.01.007)

[2. (Kang2005Human) Sung Gyun Kang, Mariana N. Dimitrova, Joaquin Ortega, Ann Ginsburg, and Michael R. Maurizi. Human mitochondrial clpp is a stable heptamer that assembles into a tetradecamer in the presence of clpx. Journal of Biological Chemistry, 280(42):35424–35432, October 2005. URL: http://dx.doi.org/10.1074/jbc.m507240200, doi:10.1074/jbc.m507240200. This article has 102 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m507240200)

[3. (Nouri2020Mitochondrial) Kazem Nouri, Yue Feng, and Aaron D. Schimmer. Mitochondrial clpp serine protease-biological function and emerging target for cancer therapy. Cell Death & Disease, October 2020. URL: http://dx.doi.org/10.1038/s41419-020-03062-z, doi:10.1038/s41419-020-03062-z. This article has 68 citations.](https://doi.org/10.1038/s41419-020-03062-z)

[4. (Brodie2018Perrault) Erica J. Brodie, Hanmiao Zhan, Tamanna Saiyed, Kaye N. Truscott, and David A. Dougan. Perrault syndrome type 3 caused by diverse molecular defects in clpp. Scientific Reports, August 2018. URL: http://dx.doi.org/10.1038/s41598-018-30311-1, doi:10.1038/s41598-018-30311-1. This article has 28 citations and is from a peer-reviewed journal.](https://doi.org/10.1038/s41598-018-30311-1)

[5. (Ahmed2015Exome) Saleem Ahmed, Musharraf Jelani, Nuha Alrayes, Hussein Sheikh Ali Mohamoud, Mona Mohammad Almramhi, Wasim Anshasi, Naushad Ali Basheer Ahmed, Jun Wang, Jamal Nasir, and Jumana Yousuf Al-Aama. Exome analysis identified a novel missense mutation in the clpp gene in a consanguineous saudi family expanding the clinical spectrum of perrault syndrome type-3. Journal of the Neurological Sciences, 353(1–2):149–154, June 2015. URL: http://dx.doi.org/10.1016/j.jns.2015.04.038, doi:10.1016/j.jns.2015.04.038. This article has 36 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.jns.2015.04.038)

[6. (Gispert2013Loss) S. Gispert, D. Parganlija, M. Klinkenberg, S. Drose, I. Wittig, M. Mittelbronn, P. Grzmil, S. Koob, A. Hamann, M. Walter, F. Buchel, T. Adler, M. Hrabe de Angelis, D. H. Busch, A. Zell, A. S. Reichert, U. Brandt, H. D. Osiewacz, M. Jendrach, and G. Auburger. Loss of mitochondrial peptidase clpp leads to infertility, hearing loss plus growth retardation via accumulation of clpx, mtdna and inflammatory factors. Human Molecular Genetics, 22(24):4871–4887, July 2013. URL: http://dx.doi.org/10.1093/hmg/ddt338, doi:10.1093/hmg/ddt338. This article has 158 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1093/hmg/ddt338)

[7. (Theunissen2016Specific) Tom E. J. Theunissen, Radek Szklarczyk, Mike Gerards, Debby M. E. I. Hellebrekers, Elvira N. M. Mulder-Den Hartog, Jo Vanoevelen, Rick Kamps, Bart de Koning, S. Lane Rutledge, Thomas Schmitt-Mechelke, Carola G. M. van Berkel, Marjo S. van der Knaap, Irenaeus F. M. de Coo, and Hubert J. M. Smeets. Specific mri abnormalities reveal severe perrault syndrome due to clpp defects. Frontiers in Neurology, November 2016. URL: http://dx.doi.org/10.3389/fneur.2016.00203, doi:10.3389/fneur.2016.00203. This article has 24 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fneur.2016.00203)

[8. (Wang2018Mitochondrial) Tianren Wang, Elnur Babayev, Zongliang Jiang, Guangxin Li, Man Zhang, Ecem Esencan, Tamas Horvath, and Emre Seli. Mitochondrial unfolded protein response gene clpp is required to maintain ovarian follicular reserve during aging, for oocyte competence, and development of pre‐implantation embryos. Aging Cell, May 2018. URL: http://dx.doi.org/10.1111/acel.12784, doi:10.1111/acel.12784. This article has 77 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1111/acel.12784)

[9. (Becker2018CLPP) Christina Becker, Alexandra Kukat, Karolina Szczepanowska, Steffen Hermans, Katharina Senft, Christoph Paul Brandscheid, Priyanka Maiti, and Aleksandra Trifunovic. <scp>clpp</scp> deficiency protects against metabolic syndrome but hinders adaptive thermogenesis. EMBO reports, March 2018. URL: http://dx.doi.org/10.15252/embr.201745126, doi:10.15252/embr.201745126. This article has 43 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.15252/embr.201745126)

[10. (Kang2004Crystallography) Sung Gyun Kang, Michael R. Maurizi, Mark Thompson, Timothy Mueser, and Bijan Ahvazi. Crystallography and mutagenesis point to an essential role for the n-terminus of human mitochondrial clpp. Journal of Structural Biology, 148(3):338–352, December 2004. URL: http://dx.doi.org/10.1016/j.jsb.2004.07.004, doi:10.1016/j.jsb.2004.07.004. This article has 98 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.jsb.2004.07.004)

[11. (Deepa2016Downregulation) Sathyaseelan S. Deepa, Shylesh Bhaskaran, Rojina Ranjit, Rizwan Qaisar, Binoj C. Nair, Yuhong Liu, Michael E. Walsh, Wilson C. Fok, and Holly Van Remmen. Down-regulation of the mitochondrial matrix peptidase clpp in muscle cells causes mitochondrial dysfunction and decreases cell proliferation. Free Radical Biology and Medicine, 91:281–292, February 2016. URL: http://dx.doi.org/10.1016/j.freeradbiomed.2015.12.021, doi:10.1016/j.freeradbiomed.2015.12.021. This article has 70 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.freeradbiomed.2015.12.021)

[12. (Alexopoulos2012ClpP:) John A. Alexopoulos, Alba Guarné, and Joaquin Ortega. Clpp: a structurally dynamic protease regulated by aaa+ proteins. Journal of Structural Biology, 179(2):202–210, August 2012. URL: http://dx.doi.org/10.1016/j.jsb.2012.05.003, doi:10.1016/j.jsb.2012.05.003. This article has 106 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.jsb.2012.05.003)

[13. (Jenkinson2013Perrault) Emma M. Jenkinson, Atteeq U. Rehman, Tom Walsh, Jill Clayton-Smith, Kwanghyuk Lee, Robert J. Morell, Meghan C. Drummond, Shaheen N. Khan, Muhammad Asif Naeem, Bushra Rauf, Neil Billington, Julie M. Schultz, Jill E. Urquhart, Ming K. Lee, Andrew Berry, Neil A. Hanley, Sarju Mehta, Deirdre Cilliers, Peter E. Clayton, Helen Kingston, Miriam J. Smith, Thomas T. Warner, Graeme C. Black, Dorothy Trump, Julian R.E. Davis, Wasim Ahmad, Suzanne M. Leal, Sheikh Riazuddin, Mary-Claire King, Thomas B. Friedman, and William G. Newman. Perrault syndrome is caused by recessive mutations in clpp, encoding a mitochondrial atp-dependent chambered protease. The American Journal of Human Genetics, 92(4):605–613, April 2013. URL: http://dx.doi.org/10.1016/j.ajhg.2013.02.013, doi:10.1016/j.ajhg.2013.02.013. This article has 189 citations.](https://doi.org/10.1016/j.ajhg.2013.02.013)