BCS1L

Mitochondrial chaperone BCS1 (BCS1L), also known as BCS1 homolog, ubiquinol-cytochrome c reductase complex chaperone (h-BCS1), is a protein that in humans is encoded by the BCS1L gene. BCS1L is a chaperone protein involved in the assembly of Ubiquinol Cytochrome c Reductase (complex III), which is located in the inner mitochondrial membrane and is part of the electron transport chain. Mutations in this gene are associated with mitochondrial complex III deficiency (nuclear, 1), GRACILE syndrome, and Bjoernstad syndrome.[5][6][7]

BCS1L
Identifiers
Aliases	BCS1L, BCS, BCS1, BJS, FLNMS, GRACILE, Hs.6719, MC3DN1, PTD, h-BCS, h-BCS1, BCS1 homolog, ubiquinol-cytochrome c reductase complex chaperone
External IDs	OMIM: 603647 MGI: 1914071 HomoloGene: 3193 GeneCards: BCS1L
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2q35 Start 218,658,764 bp[1] End 218,663,443 bp[1]
Gene location (Mouse) Chr. Chromosome 1 (mouse)[2] Band 1|1 C3 Start 74,588,289 bp[2] End 74,592,443 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • nucleotide binding • GO:0001948 protein binding • ATP binding Cellular component • mitochondrial respiratory chain complex III • mitochondrial inner membrane • integral component of membrane • membrane • mitochondrion Biological process • mitochondrion organization • mitochondrial respiratory chain complex III assembly • mitochondrial respiratory chain complex IV assembly • mitochondrial respiratory chain complex I assembly Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	617	66821
Ensembl	ENSG00000074582	ENSMUSG00000026172
UniProt	Q9Y276	Q9CZP5
RefSeq (mRNA)	NM_001079866 NM_001257342 NM_001257343 NM_001257344 NM_004328 NM_001318836 NM_001320717	NM_025784 NM_001305652
RefSeq (protein)	NP_001073335 NP_001244271 NP_001244272 NP_001244273 NP_001305765 NP_001307646 NP_004319 NP_001358372 NP_001358373 NP_001358375 NP_001358376 NP_001358377 NP_001358378 NP_001358379 NP_001358380 NP_001358381 NP_001358382 NP_001358383 NP_001358384 NP_001358385 NP_001361014 NP_001361015	NP_001292581 NP_080060
Location (UCSC)	Chr 2: 218.66 – 218.66 Mb	Chr 1: 74.59 – 74.59 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

BCS1 N-terminal domain
Identifiers
Symbol	BCS1_N
Pfam	PF08740
InterPro	IPR014851
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Structure

BCS1L is located on the q arm of chromosome 2 in position 35 and has 10 exons.[5] The BCS1L gene produces a 47.5 kDa protein composed of 419 amino acids.[8][9] The protein encoded by BCS1L belongs to the AAA ATPase family, BCS1 subfamily. BCS1L is a phosphoprotein and chaperone for Ubiquinol Cytochrome c Reductase assembly. It contains a nucleotide binding site for ATP-binding.[6][7] BCS1L does not contain a mitochondrial targeting sequence but experimental studies confirm that it is imported into mitochondria. A conserved domain at the N-terminus of BCS1L is responsible for the import and intramitochondrial sorting.[10] Associating to the inner mitochondrial membrane, BCS1L has a transmembrane domain in between two topological domains, passing through the inner mitochondrial membrane once. The majority of the protein is in the mitochondrial matrix.[6][7] Several alternatively spliced transcripts encoding two different isoforms have been described.[11]

Function

BCS1L encodes a protein that is located in the inner mitochondrial membrane and involved in the assembly of Ubiquinol Cytochrome c Reductase (complex III). Complex III plays an important role in the mitochondrial respiratory chain by transferring electrons from the Rieske iron-sulfur protein to cytochrome c. BCS1L is essential for this process through its role in the maintenance of mitochondrial tubular networks, respiratory chain assembly, and formation of the LETM1 complex.[12][6][7]

Clinical Significance

Variants of BCS1L have been associated with mitochondrial complex III deficiency, nuclear 1, GRACILE syndrome, and Bjoernstad syndrome. Mitochondrial complex III deficiency, nuclear 1 is a disorder of the mitochondrial respiratory chain resulting in reduced complex III activity and highly variable clinical features usually resulting in multi-system organ failure. Clinical features may include mitochondrial encephalopathy, psychomotor retardation, ataxia, severe failure to thrive, liver dysfunction, renal tubulopathy, muscle weakness, exercise intolerance, lactic acidosis, hypotonia, seizures, and optic atrophy. Pathogenic mutations have included R45C, R56X,[13][14][15] T50A,[16] R73C,[17] P99L, R155P, V353M,[18] G129R,[19][20] R183C, F368I,[17] and S277N. These mutations tend to affect the ATP-binding residues of BCS1L.[21][7][6]

Growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death (GRACILE) is a recessively inherited lethal disease that results in mutli-system organ failure. GRACILE is characterized by fetal growth retardation, lactic acidosis, aminoaciduria, cholestasis, and abnormalities in iron metabolism. Pathogenic mutations have included S78G, R144Q, and V327A.[22][7][6]

Bjoernstad syndrome ia an autosomal recessive disease primarily affecting hearing. This disease is characterized by congenital hearing loss and twisted hairs, a condition known as pili torti, in which hair shafts are flattened at irregular intervals and twisted 180 degrees from the normal axis, making the hair extremely brittle. Pathogenic mutations have included Y301N,[23] R184C,[17] G35R, R114W, R183H, Q302E, and R306H. These mutations tend to affect the protein-protein interactions of BCS1L.[21][7][6]

Interactions

BCS1L has 11 protein-protein interactions with 8 of them being co-complex interactions. BCS1L has been found to interact with LETM1, DNAJA1, and DDX24.[24]

See also

• Björnstad syndrome
• GRACILE syndrome

References

1. GRCh38: Ensembl release 89: ENSG00000074582 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000026172 - Ensembl, May 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.
5. "BCS1L BCS1 homolog, ubiquinol-cytochrome c reductase complex chaperone [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-08-03. This article incorporates text from this source, which is in the public domain.
6. "BCS1L - Mitochondrial chaperone BCS1 - Homo sapiens (Human) - BCS1L gene & protein". www.uniprot.org. Retrieved 2018-08-03. This article incorporates text available under the CC BY 4.0 license.
7. "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC 5210571. PMID 27899622.
8. Yao D. "Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information". amino.heartproteome.org. Archived from the original on 2018-08-04. Retrieved 2018-08-02.
9. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, et al. (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
10. Stan T, Brix J, Schneider-Mergener J, Pfanner N, Neupert W, Rapaport D (April 2003). "Mitochondrial protein import: recognition of internal import signals of BCS1 by the TOM complex". Molecular and Cellular Biology. 23 (7): 2239–50. doi:10.1128/MCB.23.7.2239-2250.2003. PMC 150725. PMID 12640110.
11. "Entrez Gene: BCS1L BCS1-like (yeast)".
12. Tamai S, Iida H, Yokota S, Sayano T, Kiguchiya S, Ishihara N, Hayashi J, Mihara K, Oka T (August 2008). "Characterization of the mitochondrial protein LETM1, which maintains the mitochondrial tubular shapes and interacts with the AAA-ATPase BCS1L". Journal of Cell Science. 121 (Pt 15): 2588–600. doi:10.1242/jcs.026625. PMID 18628306.
13. De Meirleir L, Seneca S, Damis E, Sepulchre B, Hoorens A, Gerlo E, et al. (August 2003). "Clinical and diagnostic characteristics of complex III deficiency due to mutations in the BCS1L gene". American Journal of Medical Genetics. Part A. 121A (2): 126–31. doi:10.1002/ajmg.a.20171. PMID 12910490.
14. Ramos-Arroyo MA, Hualde J, Ayechu A, De Meirleir L, Seneca S, Nadal N, Briones P (June 2009). "Clinical and biochemical spectrum of mitochondrial complex III deficiency caused by mutations in the BCS1L gene". Clinical Genetics. 75 (6): 585–7. doi:10.1111/j.1399-0004.2009.01160.x. PMID 19508421.
15. Gil-Borlado MC, González-Hoyuela M, Blázquez A, García-Silva MT, Gabaldón T, Manzanares J, Vara J, Martín MA, Seneca S, Arenas J, Ugalde C (September 2009). "Pathogenic mutations in the 5' untranslated region of BCS1L mRNA in mitochondrial complex III deficiency". Mitochondrion. 9 (5): 299–305. doi:10.1016/j.mito.2009.04.001. PMID 19389488.
16. Blázquez A, Gil-Borlado MC, Morán M, Verdú A, Cazorla-Calleja MR, Martín MA, Arenas J, Ugalde C (February 2009). "Infantile mitochondrial encephalomyopathy with unusual phenotype caused by a novel BCS1L mutation in an isolated complex III-deficient patient". Neuromuscular Disorders. 19 (2): 143–6. doi:10.1016/j.nmd.2008.11.016. PMID 19162478.
17. Fernandez-Vizarra E, Bugiani M, Goffrini P, Carrara F, Farina L, Procopio E, Donati A, Uziel G, Ferrero I, Zeviani M (May 2007). "Impaired complex III assembly associated with BCS1L gene mutations in isolated mitochondrial encephalopathy". Human Molecular Genetics. 16 (10): 1241–52. doi:10.1093/hmg/ddm072. PMID 17403714.
18. de Lonlay P, Valnot I, Barrientos A, Gorbatyuk M, Tzagoloff A, Taanman JW, Benayoun E, Chrétien D, Kadhom N, Lombès A, de Baulny HO, Niaudet P, Munnich A, Rustin P, Rötig A (September 2001). "A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure". Nature Genetics. 29 (1): 57–60. doi:10.1038/ng706. PMID 11528392.
19. Al-Owain M, Colak D, Albakheet A, Al-Younes B, Al-Humaidi Z, Al-Sayed M, et al. (September 2013). "Clinical and biochemical features associated with BCS1L mutation". Journal of Inherited Metabolic Disease. 36 (5): 813–20. doi:10.1007/s10545-012-9536-4. PMID 22991165.
20. Tuppen HA, Fehmi J, Czermin B, Goffrini P, Meloni F, Ferrero I, He L, Blakely EL, McFarland R, Horvath R, Turnbull DM, Taylor RW (August 2010). "Long-term survival of neonatal mitochondrial complex III deficiency associated with a novel BCS1L gene mutation". Molecular Genetics and Metabolism. 100 (4): 345–8. doi:10.1016/j.ymgme.2010.04.010. PMID 20472482.
21. Hinson JT, Fantin VR, Schönberger J, Breivik N, Siem G, McDonough B, et al. (February 2007). "Missense mutations in the BCS1L gene as a cause of the Björnstad syndrome". The New England Journal of Medicine. 356 (8): 809–19. doi:10.1056/NEJMoa055262. PMID 17314340.
22. Visapää I, Fellman V, Vesa J, Dasvarma A, Hutton JL, Kumar V, Payne GS, Makarow M, Van Coster R, Taylor RW, Turnbull DM, Suomalainen A, Peltonen L (October 2002). "GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L". American Journal of Human Genetics. 71 (4): 863–76. doi:10.1086/342773. PMC 378542. PMID 12215968.
23. Siddiqi S, Siddiq S, Mansoor A, Oostrik J, Ahmad N, Kazmi SA, Kremer H, Qamar R, Schraders M (December 2013). "Novel mutation in AAA domain of BCS1L causing Bjornstad syndrome". Journal of Human Genetics. 58 (12): 819–21. doi:10.1038/jhg.2013.101. PMID 24172246.
24. "14 binary interactions found for search term BCS1L". IntAct Molecular Interaction Database. EMBL-EBI. Retrieved 2018-08-25.

External links

• Human BCS1L genome location and BCS1L gene details page in the UCSC Genome Browser.

Further reading

• Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Fölsch H, Guiard B, Neupert W, Stuart RA (February 1996). "Internal targeting signal of the BCS1 protein: a novel mechanism of import into mitochondria". The EMBO Journal. 15 (3): 479–87. doi:10.1002/j.1460-2075.1996.tb00380.x. PMC 449966. PMID 8599931.
• Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA (April 1996). "A "double adaptor" method for improved shotgun library construction". Analytical Biochemistry. 236 (1): 107–13. doi:10.1006/abio.1996.0138. PMID 8619474.
• Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA (April 1997). "Large-scale concatenation cDNA sequencing". Genome Research. 7 (4): 353–8. doi:10.1101/gr.7.4.353. PMC 139146. PMID 9110174.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Lubianca Neto JF, Lu L, Eavey RD, Flores MA, Caldera RM, Sangwatanaroj S, Schott JJ, McDonough B, Santos JI, Seidman CE, Seidman JG (May 1998). "The Bjornstad syndrome (sensorineural hearing loss and pili torti) disease gene maps to chromosome 2q34-36". American Journal of Human Genetics. 62 (5): 1107–12. doi:10.1086/301837. PMC 1377094. PMID 9545407.
• Visapää I, Fellman V, Varilo T, Palotie A, Raivio KO, Peltonen L (November 1998). "Assignment of the locus for a new lethal neonatal metabolic syndrome to 2q33-37". American Journal of Human Genetics. 63 (5): 1396–403. doi:10.1086/302123. PMC 1377549. PMID 9792866.
• Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S (January 2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Research. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.