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词条 SDHAF1
释义

  1. Structure

  2. Function

  3. Clinical Significance

  4. Interactions

  5. References

  6. Further reading

{{Infobox gene}}Succinate dehydrogenase complex assembly factor 1 (SDHAF1), also known as LYR motif-containing protein 8 (LYRM8), is a protein that in humans is encoded by the SDHAF1, or LYRM8, gene. SDHAF1 is a chaperone protein involved in the assembly of the succinate dehydrogenase (SDH) complex (complex II). Mutations in this gene are associated with SDH-defective infantile leukoencephalopathy and mitochondrial complex II deficiency.[1][2][2]

Structure

SDHAF1 is located on the q arm of chromosome 19 in position 13.12 and has 1 exon.[1] The SDHAF1 gene produces a 12.8 kDa protein composed of 115 amino acids.[3][4] SDHAF1 is ubiquitously expressed and belongs to the complex I LYR family and SDHAF1 subfamily.[5] As such, SDHAF1 is one of at least eight proteins that has a LYR tripeptide motif, thought to be important for Fe-S metabolism.[6] SDHAF1 also contains an N-terminal mitochondrial targeting sequence that does not get cleaved following import into the mitochondria. The encoded protein is fairly hydrophilic and does not contain a transmembrane domain.[7]

Function

SDHAF1 is essential for the assembly of the succinate dehydrogenase (SDH) complex (complex II), an enzyme complex that is a component of both the tricarboxylic acid (TCA) cycle and the mitochondrial electron transport chain, and which couples the oxidation of succinate to fumarate with the reduction of ubiquinone (coenzyme Q) to ubiquinol.[5] The succinate dehydrogenase (SDH) complex of the mitochondrial respiratory chain is composed of 4 individual subunits. The protein encoded by the SDHAF1 gene resides in the mitochondria, and is essential for SDH assembly, but does not physically associate with the complex in vivo.[1] Specifically, SDHAF1 mediates and promotes the maturation of the SDHB subunit of the SDH catalytic dimer. The iron-sulfur (Fe-S) protein subunit SDHB is required for functional succinate dehydrogenase. By protecting SDHB from damaging oxidants, SDHAF1 plays a vital role in the assembly and stability of succinate dehydrogenase (SDH).[8][7][5] Alternatively, SDHAF1 may facilitate Fe-S cluster acquisition by SDHB by directly binding to the co-chaperone HSC20, which is an essential component of the Fe-S biogenesis machinery that facilitates transfer of the Fe-S prosthetic group from the main scaffold protein ISCU to recipient apo-proteins (i.e. SDHB),[6]

Clinical Significance

Variants of SDHAF1 have been associated with mitochondrial complex II deficiency and infantile leukoencephalopathy. Mitochondrial complex II deficiency is a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations. Clinical features include psychomotor regression in infants, poor growth with lack of speech development, severe spastic quadriplegia, dystonia, progressive leukoencephalopathy, muscle weakness, exercise intolerance, and cardiomyopathy. Some patients manifest Leigh syndrome or Kearns-Sayre syndrome. Missense mutations c.164 G > C, p.Arg55Pro and c.170 G > A, p.Gly57Glu, homozygous transversion 169G-C, p. Gly57-Arg, homozygous non sense mutation c.103G>T (p.Glu35X), and homozygous nonsense mutation c.22C > T, p.Gln8X have been associated with mitochondrial complex II deficiency due to SDHAF1 disfunction.[5][7][9][6]

Interactions

SDHAF1 has 27 protein-protein interactions with 15 of them being co-complex interactions. HSCB, SDHB, ccdc136, KRT27, CIDEB, HSPA9, and ISCU have all been found to interact with SDHAF1.[10][6]

References

1. ^1 2 {{cite web |url= https://www.ncbi.nlm.nih.gov/gene/644096 |title=Entrez Gene: Succinate dehydrogenase complex assembly factor 1 |access-date=2018-07-30 }}
2. ^{{cite journal | vauthors = Maio N, Ghezzi D, Verrigni D, Rizza T, Bertini E, Martinelli D, Zeviani M, Singh A, Carrozzo R, Rouault TA | title = Disease-Causing SDHAF1 Mutations Impair Transfer of Fe-S Clusters to SDHB | journal = Cell Metabolism | volume = 23 | issue = 2 | pages = 292–302 | date = February 2016 | pmid = 26749241 | pmc = 4749439 | doi = 10.1016/j.cmet.2015.12.005 }}
3. ^{{cite journal | vauthors = Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P | display-authors = 6 | title = Integration of cardiac proteome biology and medicine by a specialized knowledgebase | journal = Circulation Research | volume = 113 | issue = 9 | pages = 1043–53 | date = October 2013 | pmid = 23965338 | pmc = 4076475 | doi = 10.1161/CIRCRESAHA.113.301151 }}
4. ^{{cite web |url= https://amino.heartproteome.org/web/protein/A6NFY7 |title=Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information|last=Yao|first=Daniel | name-list-format = vanc |website=amino.heartproteome.org|access-date=2018-07-30}}
5. ^1 2 3 4 {{UniProt Full|A6NFY7|SDHAF1}} {{cite journal | author = The UniProt Consortium | title = UniProt: the universal protein knowledgebase | journal = Nucleic Acids Research | volume = 45 | issue = D1 | pages = D158–D169 | date = January 2017 | pmid = 27899622 | pmc = 5210571 | doi = 10.1093/nar/gkw1099 }}
6. ^1 2 3 {{cite journal | vauthors = Maio N, Ghezzi D, Verrigni D, Rizza T, Bertini E, Martinelli D, Zeviani M, Singh A, Carrozzo R, Rouault TA | title = Disease-Causing SDHAF1 Mutations Impair Transfer of Fe-S Clusters to SDHB | journal = Cell Metabolism | volume = 23 | issue = 2 | pages = 292–302 | date = February 2016 | pmid = 26749241 | pmc = 4749439 | doi = 10.1016/j.cmet.2015.12.005 }}
7. ^1 2 {{cite journal | vauthors = Ghezzi D, Goffrini P, Uziel G, Horvath R, Klopstock T, Lochmüller H, D'Adamo P, Gasparini P, Strom TM, Prokisch H, Invernizzi F, Ferrero I, Zeviani M | title = SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated in SDH-defective infantile leukoencephalopathy | journal = Nature Genetics | volume = 41 | issue = 6 | pages = 654–6 | date = June 2009 | pmid = 19465911 | doi = 10.1038/ng.378 }}
8. ^{{cite journal | vauthors = Na U, Yu W, Cox J, Bricker DK, Brockmann K, Rutter J, Thummel CS, Winge DR | title = The LYR factors SDHAF1 and SDHAF3 mediate maturation of the iron-sulfur subunit of succinate dehydrogenase | journal = Cell Metabolism | volume = 20 | issue = 2 | pages = 253–66 | date = August 2014 | pmid = 24954417 | pmc = 4126850 | doi = 10.1016/j.cmet.2014.05.014 }}
9. ^{{cite journal | vauthors = Ohlenbusch A, Edvardson S, Skorpen J, Bjornstad A, Saada A, Elpeleg O, Gärtner J, Brockmann K | title = Leukoencephalopathy with accumulated succinate is indicative of SDHAF1 related complex II deficiency | journal = Orphanet Journal of Rare Diseases | volume = 7 | pages = 69 | date = September 2012 | pmid = 22995659 | pmc = 3492161 | doi = 10.1186/1750-1172-7-69 }}
10. ^{{cite web | url = https://www.ebi.ac.uk/intact/interactions?conversationContext=3&query=SDHAF1 | title = 27 binary interactions found for search term SDHAF1 | work = IntAct Molecular Interaction Database | publisher = EMBL-EBI | access-date = 2018-08-25 }}

Further reading

{{refbegin|2}}
  • {{cite journal | vauthors = Hoekstra AS, Bayley JP | title = The role of complex II in disease | journal = Biochimica et Biophysica Acta | volume = 1827 | issue = 5 | pages = 543–51 | date = May 2013 | pmid = 23174333 | doi = 10.1016/j.bbabio.2012.11.005 }}
{{refend}}{{NLM content}}{{Portal bar|Mitochondria|Gene Wiki}}

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