ClpX

CLPX
Identifikatori
Aliasi	CLPX
Vanjski ID-jevi	OMIM: 615611 MGI: 1346017 HomoloGene: 4851 GeneCards: CLPX
Lokacija gena (čovjek)
Hrom.	Hromosom 15 (čovjek)
Kraj	65,185,342 bp
Lokacija gena (miš)
Hrom.	Hromosom 9 (miš)
Kraj	65,237,940 bp
Ontologija gena
Molekularna funkcija	• unfolded protein binding; • nucleotide binding; • GO:0001948, GO:0016582 vezivanje za proteine; • peptidase activator activity; • vezivanje iona metala; • ATP-dependent peptidase activity; • ATPase activity; • ATP binding;
Ćelijska komponenta	• mitochondrial endopeptidase Clp complex; • mitochondrial matrix; • nukleoplazma; • endopeptidase Clp complex; • mitochondrial nucleoid; • mitohondrija; • citosol; • mitochondrial inner membrane;
Biološki proces	• proteolysis involved in cellular protein catabolic process; • Savijanje proteina; • positive regulation of peptidase activity; • ATP metabolic process; • GO:0044257 protein catabolic process;
	Izvori:Amigo / QuickGO
Ortolozi
	10845
	270166
	ENSG00000166855
	ENSMUSG00000015357
	O76031
	Q9JHS4
	NM_006660
	NM_001044389; NM_011802
	NP_006651; NP_006651.2
	NP_001037854; NP_035932
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

ATP-ovisna Clp proteaza, podjedinica mitohondrijke ATP-vezujućeg clpX-u sličnog proteina, je enzim koji je kod ljudi kodiran genom CLPX. Ovaj protein je član porodice AAA proteina (AAA + ATPaza) i treba da formira proteinski kompleks Clp proteaze (endopeptidaza Clp).

Struktura

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 633 aminokiseline, a molekulska težina 69.224 Da.^[5].

10	20	30	40	50
MPSCGACTCG	AAAVRLITSS	LASAQRGISG	GRIHMSVLGR	LGTFETQILQ
RAPLRSFTET	PAYFASKDGI	SKDGSGDGNK	KSASEGSSKK	SGSGNSGKGG
NQLRCPKCGD	LCTHVETFVS	STRFVKCEKC	HHFFVVLSEA	DSKKSIIKEP
ESAAEAVKLA	FQQKPPPPPK	KIYNYLDKYV	VGQSFAKKVL	SVAVYNHYKR
IYNNIPANLR	QQAEVEKQTS	LTPRELEIRR	REDEYRFTKL	LQIAGISPHG
NALGASMQQQ	VNQQIPQEKR	GGEVLDSSHD	DIKLEKSNIL	LLGPTGSGKT
LLAQTLAKCL	DVPFAICDCT	TLTQAGYVGE	DIESVIAKLL	QDANYNVEKA
QQGIVFLDEV	DKIGSVPGIH	QLRDVGGEGV	QQGLLKLLEG	TIVNVPEKNS
RKLRGETVQV	DTTNILFVAS	GAFNGLDRII	SRRKNEKYLG	FGTPSNLGKG
RRAAAAADLA	NRSGESNTHQ	DIEEKDRLLR	HVEARDLIEF	GMIPEFVGRL
PVVVPLHSLD	EKTLVQILTE	PRNAVIPQYQ	ALFSMDKCEL	NVTEDALKAI
ARLALERKTG	ARGLRSIMEK	LLLEPMFEVP	NSDIVCVEVD	KEVVEGKKEP
GYIRAPTKES	SEEEYDSGVE	EEGWPRQADA	ANS

Simboli

C: Cistein
D: Asparaginska kiselina
E: Glutaminska kiselina
F: Fenilalanin
G: Glicin
H: Histidin
I: Izoleucin
K: Lizin
L: Leucin
M: Metionin
N: Asparagin
P: Prolin
Q: Glutamin
R: Arginin
S: Serin
T: Treonin
V: Valin
W: Triptofan
Y: Tirozin

Struktura proteina

Znanje o ljudskom proteinu ClpX uglavnom se temelji na istraživanjima o proteinu E. coli. Monomer proteina ClpX u E. coli sadrži N-terminalni domen i AAA + modul koji se sastoji od velikog i malog AAA + domena.^[6]

Složeni sklop

Tokom sastavljanja kompleksa proteaze Clp, podjedinice ClpX čine heksamernu prstenastu strukturu. Prema orijentaciji ClpX podjedinica unutar prstenaste strukture, mogu se svrstati u dvije klase: "učitavajuća" (L podjedinica) i "nučitavajuća" podjedinica (U podjedinica). U L podjedinici, veliki i mali AAA + domen čine pukotinu za vezivanje [[nukleotid]nog ATP ili ADP. Međutim, veliki i mali AAA + domeni u U podjedinici rotiraju se za ~80 °, što sprečava vezivanje nukleotida. Kada se okupe u heksamerni prsten, L i U podjedinice čine obrazac "L-L-U-L-L-U", koji ima maksimalan kapacitet da veže po četiri ATP ili ADP.^[7] Elektronsko-mikroskopske studije (EM) pokazale su da se strukture prstena ClpX slažu koaksijalno na obje strane ili na obje strane kompleksa tetradekamera ClpP, da bi stvorile komplekse proteaze ClpXP. ATP vezivanje može stabilizirati povezanost između struktura ClpX i ClpP prstena.

Kod mikobakterija, ClpXP proteaza se sastoji od komponente ATPaza (ClpX) i dva proteina ClpP (ClpP1 i ClpP2).^[8]^[9] Zanimljivo je da, za razliku od E. coli, u kojoj je poznato da se ATPazna komponenta veže za bilo koju stranu komponente peptidaze u obliku bačve, mikobakterijska komponent ATPase (ClpX) pristaje na asimetričan način, vežući se samo za jedno stranu kompleksa ClpP1P2 - tj. ClpP2.^[10]^[11]

Funkcija

ClpX je ATP-ovisni šaperon koji može prepoznati proteinske supstrate vežući se na oznake razgradnje proteina. Te oznake mogu biti kratke nestrukturirane peptidne sekvence (npr. SsrA-oznaka u E coli). Kao bitna komponenta ClpP proteaznog kompleksa, ClpX regrutuje razgradive supstrate i razvija njihovu tercijarnu strukturu, za što je potrebna energija koju daje hidroliza ATP. Proteoliza|Nakon toga, ovi ClpX šaperoni prenose proteinske supstrate u [proteolitsku]] komoru koju formira ClpP tetradekamer.

Klinički značaj

Kod sisara, ClpXP proteaza ima ključni doprinos u kontroli kvaliteta mitohondrijskog proteina. Kompromitovana funkcija ClpXP obično dovodi do akumulacije oštećenih proteina i mitohondrijskih disfunkcija, što je vjerovatno potencijalni uzrok neurodegenerativnih bolesti i starenja.^[12]

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000166855 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000015357 - Ensembl, maj 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "UniProt, O76031". Pristupljeno 13. 7. 2021.
^ Glynn SE, Nager AR, Baker TA, Sauer RT (maj 2012). "Dynamic and static components power unfolding in topologically closed rings of a AAA+ proteolytic machine". Nature Structural & Molecular Biology. 19 (6): 616–22. doi:10.1038/nsmb.2288. PMC 3372766. PMID 22562135.
^ Baker TA, Sauer RT (januar 2012). "ClpXP, an ATP-powered unfolding and protein-degradation machine". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1823 (1): 15–28. doi:10.1016/j.bbamcr.2011.06.007. PMC 3209554. PMID 21736903.
^ Akopian T, Kandror O, Raju RM, Unnikrishnan M, Rubin EJ, Goldberg AL (mart 2012). "The active ClpP protease from M. tuberculosis is a complex composed of a heptameric ClpP1 and a ClpP2 ring". The EMBO Journal. 31 (6): 1529–41. doi:10.1038/emboj.2012.5. PMC 3321190. PMID 22286948.
^ Schmitz KR, Carney DW, Sello JK, Sauer RT (oktobar 2014). "Crystal structure of Mycobacterium tuberculosis ClpP1P2 suggests a model for peptidase activation by AAA+ partner binding and substrate delivery". Proceedings of the National Academy of Sciences of the United States of America. 111 (43): E4587-95. Bibcode:2014PNAS..111E4587S. doi:10.1073/pnas.1417120111. PMC 4217457. PMID 25267638.
^ Leodolter J, Warweg J, Weber-Ban E (1. 5. 2015). Zeth K (ured.). "The Mycobacterium tuberculosis ClpP1P2 Protease Interacts Asymmetrically with Its ATPase Partners ClpX and ClpC1". PLOS ONE. 10 (5): e0125345. Bibcode:2015PLoSO..1025345L. doi:10.1371/journal.pone.0125345. PMC 4416901. PMID 25933022.
^ Nagpal J, Paxman JJ, Zammit JE, Alhuwaider A, Truscott KN, Heras B, Dougan DA (decembar 2019). "Molecular and structural insights into an asymmetric proteolytic complex (ClpP1P2) from Mycobacterium smegmatis". Scientific Reports. 9 (1): 18019. Bibcode:2019NatSR...918019N. doi:10.1038/s41598-019-53736-8. PMC 6889138. PMID 31792243.
^ Hamon MP, Bulteau AL, Friguet B (septembar 2015). "Mitochondrial proteases and protein quality control in ageing and longevity". Ageing Research Reviews. 23 (Pt A): 56–66. doi:10.1016/j.arr.2014.12.010. PMID 25578288. S2CID 205667759.

Portal Biologija

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000166855 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000015357 - Ensembl, maj 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[UniProt-5] "UniProt, O76031". Pristupljeno 13. 7. 2021.

[6] Glynn SE, Nager AR, Baker TA, Sauer RT (maj 2012). "Dynamic and static components power unfolding in topologically closed rings of a AAA+ proteolytic machine". Nature Structural & Molecular Biology. 19 (6): 616–22. doi:10.1038/nsmb.2288. PMC 3372766. PMID 22562135.

[7] Baker TA, Sauer RT (januar 2012). "ClpXP, an ATP-powered unfolding and protein-degradation machine". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1823 (1): 15–28. doi:10.1016/j.bbamcr.2011.06.007. PMC 3209554. PMID 21736903.

[8] Akopian T, Kandror O, Raju RM, Unnikrishnan M, Rubin EJ, Goldberg AL (mart 2012). "The active ClpP protease from M. tuberculosis is a complex composed of a heptameric ClpP1 and a ClpP2 ring". The EMBO Journal. 31 (6): 1529–41. doi:10.1038/emboj.2012.5. PMC 3321190. PMID 22286948.

[9] Schmitz KR, Carney DW, Sello JK, Sauer RT (oktobar 2014). "Crystal structure of Mycobacterium tuberculosis ClpP1P2 suggests a model for peptidase activation by AAA+ partner binding and substrate delivery". Proceedings of the National Academy of Sciences of the United States of America. 111 (43): E4587-95. Bibcode:2014PNAS..111E4587S. doi:10.1073/pnas.1417120111. PMC 4217457. PMID 25267638.

[10] Leodolter J, Warweg J, Weber-Ban E (1. 5. 2015). Zeth K (ured.). "The Mycobacterium tuberculosis ClpP1P2 Protease Interacts Asymmetrically with Its ATPase Partners ClpX and ClpC1". PLOS ONE. 10 (5): e0125345. Bibcode:2015PLoSO..1025345L. doi:10.1371/journal.pone.0125345. PMC 4416901. PMID 25933022.

[11] Nagpal J, Paxman JJ, Zammit JE, Alhuwaider A, Truscott KN, Heras B, Dougan DA (decembar 2019). "Molecular and structural insights into an asymmetric proteolytic complex (ClpP1P2) from Mycobacterium smegmatis". Scientific Reports. 9 (1): 18019. Bibcode:2019NatSR...918019N. doi:10.1038/s41598-019-53736-8. PMC 6889138. PMID 31792243.

[12] Hamon MP, Bulteau AL, Friguet B (septembar 2015). "Mitochondrial proteases and protein quality control in ageing and longevity". Ageing Research Reviews. 23 (Pt A): 56–66. doi:10.1016/j.arr.2014.12.010. PMID 25578288. S2CID 205667759.

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