AAA ATPases | Enzymes | IUPHAR/BPS Guide to PHARMACOLOGY

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AAA ATPases

AAA ATPases C

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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AAA or AAA+ (ATPases Associated with diverse cellular Activities) proteins couple chemical energy provided by ATP hydrolysis to the remodeling or translocation of macromolecules. They are involved in a wide range of cellular processes, including DNA replication, protein degradation, membrane fusion, microtubule severing, peroxisome biogenesis, signal transduction and the regulation of gene expression.

Enzymes

3180

caseinolytic mitochondrial matrix peptidase proteolytic subunit Show summary »« Hide summary

Target Id

3273

Nomenclature

caseinolytic mitochondrial matrix peptidase proteolytic subunit

Genes

CLPP (Hs), Clpp (Mm), Clpp (Rn)

Ensembl ID

ENSG00000125656 (Hs), ENSMUSG00000002660 (Mm), ENSRNOG00000047052 (Rn)

UniProtKB AC

Q16740 (Hs), O88696 (Mm)

Activators

compound 16z [PMID: 35609303] pEC₅₀ 6.7 [2]

Allosteric modulators

ONC201 (Activation) [9]

Comment

Caseinolytic mitochondrial matrix peptidase (ClpP) is an ATP-dependent protease that plays an important role in maintaining mitochondrial protein homeostasis. It is a validated target for the development of anti-tumour drugs. The functional enzyme is a complex of two identical cylindrical heptameric 'pores' of CLPP catalytic subunits that are apically capped by chaperone subunits (CLPX) that regulate substrate recognition, unfolding and translocation [3-4].

katanin catalytic subunit A1 Show summary »« Hide summary More detailed page go icon to follow link

Target Id

2912

Nomenclature

katanin catalytic subunit A1

Previous and unofficial names

katanin p60 (ATPase containing) subunit A 1 | microtubule-severing protein

Genes

KATNA1 (Hs), Katna1 (Mm), Katna1 (Rn)

Ensembl ID

ENSG00000186625 (Hs), ENSMUSG00000019794 (Mm), ENSRNOG00000014996 (Rn)

UniProtKB AC

O75449 (Hs), Q9WV86 (Mm), Q6E0V2 (Rn)

EC number

3.6.4.3	ATP + H(2)O <=> ADP + phosphate
ATP + H(2)O <=> ADP + phosphate

lon peptidase 1, mitochondrial Show summary »« Hide summary

Target Id

3180

Nomenclature

lon peptidase 1, mitochondrial

Previous and unofficial names

lon peptidase 1 | PRSS15

Genes

LONP1 (Hs), Lonp1 (Mm), Lonp1 (Rn)

Ensembl ID

ENSG00000196365 (Hs), ENSMUSG00000041168 (Mm), ENSRNOG00000046502 (Rn)

UniProtKB AC

P36776 (Hs), Q8CGK3 (Mm), Q924S5 (Rn)

EC number

3.4.21.53

Inhibitors

compound 12d [PMID: 33821636] pIC₅₀ 7.8 [5]

Comment

LONP1 is an AAA+ serine protease. It mediates the selective degradation of misfolded, unassembled or oxidatively damaged proteins in the mitochondrial matrix, and is essential for mitochondrial homeostasis. Dysregulation of LONP1 leads to disease: Loss of function leads to severe developmental complications in CODAS syndrome [1] and other mitochondrial diseases [7], whereas elevated expression exerts pro-tumourigenic effects in some cancers [6,8,10]. Homozygous LONP1 knockouts are embryonically lethal.

References

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1. Dikoglu E, Alfaiz A, Gorna M, Bertola D, Chae JH, Cho TJ, Derbent M, Alanay Y, Guran T, Kim OH et al.. (2015) Mutations in LONP1, a mitochondrial matrix protease, cause CODAS syndrome. Am J Med Genet A, 167 (7): 1501-9. [PMID:25808063]

2. Huang J, Zhang J, Luo B, Qiao W, Qiu Z, Song R, Dai Z, Sui J, Xu X, Ruan S et al.. (2022) Discovery of a Novel Series of Imipridone Compounds as Homo sapiens Caseinolytic Protease P Agonists with Potent Antitumor Activities In Vitro and In Vivo. J Med Chem, 65 (11): 7629-7655. [PMID:35609303]

3. Kang SG, Dimitrova MN, Ortega J, Ginsburg A, Maurizi MR. (2005) Human mitochondrial ClpP is a stable heptamer that assembles into a tetradecamer in the presence of ClpX. J Biol Chem, 280 (42): 35424-32. [PMID:16115876]

4. Kang SG, Ortega J, Singh SK, Wang N, Huang NN, Steven AC, Maurizi MR. (2002) Functional proteolytic complexes of the human mitochondrial ATP-dependent protease, hClpXP. J Biol Chem, 277 (23): 21095-102. [PMID:11923310]

5. Kingsley LJ, He X, McNeill M, Nelson J, Nikulin V, Ma Z, Lu W, Zhou VW, Manuia M, Kreusch A et al.. (2021) Structure-Based Design of Selective LONP1 Inhibitors for Probing In Vitro Biology. J Med Chem, 64 (8): 4857-4869. [PMID:33821636]

6. Nie X, Li M, Lu B, Zhang Y, Lan L, Chen L, Lu J. (2013) Down-regulating overexpressed human Lon in cervical cancer suppresses cell proliferation and bioenergetics. PLoS One, 8 (11): e81084. [PMID:24260536]

7. Peter B, Waddington CL, Oláhová M, Sommerville EW, Hopton S, Pyle A, Champion M, Ohlson M, Siibak T, Chrzanowska-Lightowlers ZMA et al.. (2018) Defective mitochondrial protease LonP1 can cause classical mitochondrial disease. Hum Mol Genet, 27 (10): 1743-1753. [PMID:29518248]

8. Pinti M, Gibellini L, Nasi M, De Biasi S, Bortolotti CA, Iannone A, Cossarizza A. (2016) Emerging role of Lon protease as a master regulator of mitochondrial functions. Biochim Biophys Acta, 1857 (8): 1300-1306. [PMID:27033304]

9. Prabhu VV, Morrow S, Rahman Kawakibi A, Zhou L, Ralff M, Ray J, Jhaveri A, Ferrarini I, Lee Y, Parker C et al.. (2020) ONC201 and imipridones: Anti-cancer compounds with clinical efficacy. Neoplasia, 22 (12): 725-744. [PMID:33142238]

10. Quirós PM, Español Y, Acín-Pérez R, Rodríguez F, Bárcena C, Watanabe K, Calvo E, Loureiro M, Fernández-García MS, Fueyo A et al.. (2014) ATP-dependent Lon protease controls tumor bioenergetics by reprogramming mitochondrial activity. Cell Rep, 8 (2): 542-56. [PMID:25017063]

How to cite this family page

Database page citation:

AAA ATPases. Accessed on 24/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=933.

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Fabbro D, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Enzymes. Br J Pharmacol. 180 Suppl 2:S289-373.