SDHF1_HUMAN
ID SDHF1_HUMAN Reviewed; 115 AA.
AC A6NFY7; B2RPM7;
DT 08-APR-2008, integrated into UniProtKB/Swiss-Prot.
DT 24-JUL-2007, sequence version 1.
DT 03-AUG-2022, entry version 96.
DE RecName: Full=Succinate dehydrogenase assembly factor 1, mitochondrial {ECO:0000303|PubMed:19465911};
DE Short=SDH assembly factor 1 {ECO:0000303|PubMed:19465911};
DE Short=SDHAF1 {ECO:0000303|PubMed:19465911};
DE AltName: Full=LYR motif-containing protein 8;
GN Name=SDHAF1 {ECO:0000303|PubMed:19465911, ECO:0000312|HGNC:HGNC:33867};
GN Synonyms=LYRM8;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [4]
RP FUNCTION.
RX PubMed=24954417; DOI=10.1016/j.cmet.2014.05.014;
RA Na U., Yu W., Cox J., Bricker D.K., Brockmann K., Rutter J., Thummel C.S.,
RA Winge D.R.;
RT "The LYR factors SDHAF1 and SDHAF3 mediate maturation of the iron-sulfur
RT subunit of succinate dehydrogenase.";
RL Cell Metab. 20:253-266(2014).
RN [5]
RP VARIANTS MC2DN2 PRO-55 AND ARG-57, FUNCTION, SUBCELLULAR LOCATION, AND
RP TISSUE SPECIFICITY.
RX PubMed=19465911; DOI=10.1038/ng.378;
RA Ghezzi D., Goffrini P., Uziel G., Horvath R., Klopstock T., Lochmuller H.,
RA D'Adamo P., Gasparini P., Strom T.M., Prokisch H., Invernizzi F.,
RA Ferrero I., Zeviani M.;
RT "SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated in
RT SDH-defective infantile leukoencephalopathy.";
RL Nat. Genet. 41:654-656(2009).
RN [6]
RP VARIANTS MC2DN2 8-GLN--ARG-115 DEL; PRO-55 AND ARG-57.
RX PubMed=22995659; DOI=10.1186/1750-1172-7-69;
RA Ohlenbusch A., Edvardson S., Skorpen J., Bjornstad A., Saada A.,
RA Elpeleg O., Gaertner J., Brockmann K.;
RT "Leukoencephalopathy with accumulated succinate is indicative of SDHAF1
RT related complex II deficiency.";
RL Orphanet J. Rare Dis. 7:69-69(2012).
RN [7]
RP VARIANTS MC2DN2 8-GLN--ARG-115 DEL; 52-TYR--ARG-115 DEL; PRO-55; ARG-57 AND
RP GLU-57.
RX PubMed=26642834; DOI=10.1002/ana.24572;
RG SDH Study Group;
RA Helman G., Caldovic L., Whitehead M.T., Simons C., Brockmann K.,
RA Edvardson S., Bai R., Moroni I., Taylor J.M., Van Haren K., Taft R.J.,
RA Vanderver A., van der Knaap M.S.;
RT "Magnetic resonance imaging spectrum of succinate dehydrogenase-related
RT infantile leukoencephalopathy.";
RL Ann. Neurol. 79:379-386(2016).
RN [8]
RP CHARACTERIZATION OF VARIANTS MC2DN2 PRO-55 AND ARG-57, VARIANT MC2DN2
RP 35-GLU--ARG-115 DEL, FUNCTION, INTERACTION WITH HSC20 AND SDHB, ROLE OF LYR
RP MOTIFS, AND MUTAGENESIS OF 14-LYS--ARG-16 AND 53-LYS--ARG-55.
RX PubMed=26749241; DOI=10.1016/j.cmet.2015.12.005;
RA Maio N., Ghezzi D., Verrigni D., Rizza T., Bertini E., Martinelli D.,
RA Zeviani M., Singh A., Carrozzo R., Rouault T.A.;
RT "Disease-causing SDHAF1 mutations impair transfer of Fe-S clusters to
RT SDHB.";
RL Cell Metab. 23:292-302(2016).
CC -!- FUNCTION: Plays an essential role in the assembly of succinate
CC dehydrogenase (SDH), an enzyme complex (also referred to as respiratory
CC complex II) that is a component of both the tricarboxylic acid (TCA)
CC cycle and the mitochondrial electron transport chain, and which couples
CC the oxidation of succinate to fumarate with the reduction of ubiquinone
CC (coenzyme Q) to ubiquinol (PubMed:24954417, PubMed:19465911). Promotes
CC maturation of the iron-sulfur protein subunit SDHB of the SDH catalytic
CC dimer, protecting it from the deleterious effects of oxidants
CC (PubMed:24954417). May act together with SDHAF3 (PubMed:24954417).
CC Contributes to iron-sulfur cluster incorporation into SDHB by binding
CC to SDHB and recruiting the iron-sulfur transfer complex formed by
CC HSC20, HSPA9 and ISCU through direct binding to HSC20
CC (PubMed:26749241). {ECO:0000269|PubMed:19465911,
CC ECO:0000269|PubMed:24954417, ECO:0000269|PubMed:26749241}.
CC -!- SUBUNIT: Interacts with SDHB within an SDHA-SDHB subcomplex
CC (PubMed:19465911, PubMed:26749241). Also interacts with the iron-sulfur
CC transfer complex formed by HSC20, HSPA9 and ISCU through direct binding
CC to HSC20 (PubMed:26749241). Binding of SDHAF1 to SDHB precedes and is
CC necessary for recruitment of the iron-sulfur transfer complex by SDHAF1
CC (PubMed:26749241). {ECO:0000269|PubMed:19465911,
CC ECO:0000269|PubMed:26749241}.
CC -!- INTERACTION:
CC A6NFY7; Q9UHD4: CIDEB; NbExp=3; IntAct=EBI-12011488, EBI-7062247;
CC A6NFY7; Q8IWL3: HSCB; NbExp=5; IntAct=EBI-12011488, EBI-1805738;
CC A6NFY7; Q7Z3Y8: KRT27; NbExp=3; IntAct=EBI-12011488, EBI-3044087;
CC A6NFY7; P21912: SDHB; NbExp=12; IntAct=EBI-12011488, EBI-1056481;
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix
CC {ECO:0000305|PubMed:19465911}.
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed.
CC {ECO:0000269|PubMed:19465911}.
CC -!- DISEASE: Mitochondrial complex II deficiency, nuclear type 2 (MC2DN2)
CC [MIM:619166]: A form of mitochondrial complex II deficiency, a disorder
CC with heterogeneous clinical manifestations. Some patients have
CC multisystem involvement of the brain, heart, muscle, liver, and kidneys
CC resulting in death in infancy, whereas others have only isolated
CC cardiac or muscle involvement with onset in adulthood and normal
CC cognition. Clinical features include psychomotor regression in infants,
CC poor growth with lack of speech development, severe spastic
CC quadriplegia, dystonia, progressive leukoencephalopathy, muscle
CC weakness, exercise intolerance, cardiomyopathy. Some patients manifest
CC Leigh syndrome or Kearns-Sayre syndrome. MC2DN2 inheritance is
CC autosomal recessive. {ECO:0000269|PubMed:19465911,
CC ECO:0000269|PubMed:22995659, ECO:0000269|PubMed:26642834,
CC ECO:0000269|PubMed:26749241}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: Riboflavin supplementation, which is used as a treatment
CC in SDHAF1-deficient patients, enhances SDHA flavinylation and activity
CC and reduces levels of HIF1A, HIF2A and succinate.
CC {ECO:0000269|PubMed:26749241}.
CC -!- SIMILARITY: Belongs to the complex I LYR family. SDHAF1 subfamily.
CC {ECO:0000305}.
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DR EMBL; AF038458; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC137516; AAI37517.1; -; mRNA.
DR EMBL; BC137517; AAI37518.1; -; mRNA.
DR CCDS; CCDS32999.1; -.
DR RefSeq; NP_001036096.1; NM_001042631.2.
DR AlphaFoldDB; A6NFY7; -.
DR SMR; A6NFY7; -.
DR BioGRID; 569311; 15.
DR DIP; DIP-62123N; -.
DR IntAct; A6NFY7; 6.
DR STRING; 9606.ENSP00000368165; -.
DR iPTMnet; A6NFY7; -.
DR PhosphoSitePlus; A6NFY7; -.
DR BioMuta; SDHAF1; -.
DR MassIVE; A6NFY7; -.
DR PaxDb; A6NFY7; -.
DR PeptideAtlas; A6NFY7; -.
DR PRIDE; A6NFY7; -.
DR ProteomicsDB; 1090; -.
DR TopDownProteomics; A6NFY7; -.
DR Antibodypedia; 44606; 199 antibodies from 27 providers.
DR DNASU; 644096; -.
DR Ensembl; ENST00000378887.4; ENSP00000368165.2; ENSG00000205138.4.
DR GeneID; 644096; -.
DR KEGG; hsa:644096; -.
DR MANE-Select; ENST00000378887.4; ENSP00000368165.2; NM_001042631.3; NP_001036096.2.
DR UCSC; uc002ocp.4; human.
DR CTD; 644096; -.
DR DisGeNET; 644096; -.
DR GeneCards; SDHAF1; -.
DR HGNC; HGNC:33867; SDHAF1.
DR HPA; ENSG00000205138; Low tissue specificity.
DR MalaCards; SDHAF1; -.
DR MIM; 612848; gene.
DR MIM; 619166; phenotype.
DR neXtProt; NX_A6NFY7; -.
DR OpenTargets; ENSG00000205138; -.
DR Orphanet; 3208; Isolated succinate-CoQ reductase deficiency.
DR PharmGKB; PA165394270; -.
DR VEuPathDB; HostDB:ENSG00000205138; -.
DR eggNOG; KOG4620; Eukaryota.
DR GeneTree; ENSGT00940000157289; -.
DR HOGENOM; CLU_154777_0_1_1; -.
DR InParanoid; A6NFY7; -.
DR OMA; FRENARI; -.
DR OrthoDB; 1638205at2759; -.
DR PhylomeDB; A6NFY7; -.
DR TreeFam; TF344152; -.
DR PathwayCommons; A6NFY7; -.
DR SignaLink; A6NFY7; -.
DR BioGRID-ORCS; 644096; 91 hits in 1077 CRISPR screens.
DR ChiTaRS; SDHAF1; human.
DR GenomeRNAi; 644096; -.
DR Pharos; A6NFY7; Tbio.
DR PRO; PR:A6NFY7; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; A6NFY7; protein.
DR Bgee; ENSG00000205138; Expressed in type B pancreatic cell and 205 other tissues.
DR Genevisible; A6NFY7; HS.
DR GO; GO:0005759; C:mitochondrial matrix; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0034553; P:mitochondrial respiratory chain complex II assembly; IMP:UniProtKB.
DR CDD; cd20268; Complex1_LYR_SDHAF1_LYRM8; 1.
DR InterPro; IPR008011; Complex1_LYR_dom.
DR InterPro; IPR045295; Complex1_LYR_SDHAF1_LYRM8.
DR Pfam; PF05347; Complex1_LYR; 1.
PE 1: Evidence at protein level;
KW Chaperone; Disease variant; Mitochondrion; Primary mitochondrial disease;
KW Reference proteome; Repeat.
FT CHAIN 1..115
FT /note="Succinate dehydrogenase assembly factor 1,
FT mitochondrial"
FT /id="PRO_0000327916"
FT REGION 53..65
FT /note="Interaction with SDHB"
FT /evidence="ECO:0000269|PubMed:26749241"
FT REGION 74..115
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 14..16
FT /note="LYR motif 1; required for interaction with HSC20"
FT /evidence="ECO:0000269|PubMed:26749241"
FT MOTIF 53..55
FT /note="LYR motif 2; not required for interaction with
FT HSC20"
FT /evidence="ECO:0000269|PubMed:26749241"
FT COMPBIAS 96..115
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT VARIANT 8..115
FT /note="Missing (in MC2DN2)"
FT /evidence="ECO:0000269|PubMed:22995659,
FT ECO:0000269|PubMed:26642834"
FT /id="VAR_081226"
FT VARIANT 35..115
FT /note="Missing (in MC2DN2; rapid degradation of SDHB by the
FT LONP1 protease; increased levels of HIF1A and EPAS1/HIF2A
FT which correlates with succinate accumulation)"
FT /evidence="ECO:0000269|PubMed:26749241"
FT /id="VAR_081227"
FT VARIANT 52..115
FT /note="Missing (in MC2DN2)"
FT /evidence="ECO:0000269|PubMed:26642834"
FT /id="VAR_085405"
FT VARIANT 55
FT /note="R -> P (in MC2DN2; reduces but does not prevent
FT interaction with HSC20 or SDHB; dbSNP:rs137853193)"
FT /evidence="ECO:0000269|PubMed:19465911,
FT ECO:0000269|PubMed:22995659, ECO:0000269|PubMed:26642834,
FT ECO:0000269|PubMed:26749241"
FT /id="VAR_058097"
FT VARIANT 57
FT /note="G -> E (in MC2DN2)"
FT /evidence="ECO:0000269|PubMed:26642834"
FT /id="VAR_085406"
FT VARIANT 57
FT /note="G -> R (in MC2DN2; abolishes binding to the iron-
FT sulfur transfer complex formed by HSC20, HSPA9 and ICSU;
FT prevents interaction with SDHB; leads to rapid degradation
FT of SDHAF1; dbSNP:rs137853192)"
FT /evidence="ECO:0000269|PubMed:19465911,
FT ECO:0000269|PubMed:22995659, ECO:0000269|PubMed:26642834,
FT ECO:0000269|PubMed:26749241"
FT /id="VAR_058098"
FT MUTAGEN 14..16
FT /note="LYR->AAA: Abolishes interaction with the iron-sulfur
FT transfer complex composed of HSC20, HSPA9 and ISCU and
FT reduces binding to SDHB."
FT /evidence="ECO:0000269|PubMed:26749241"
FT MUTAGEN 53..55
FT /note="LYR->AAA: Retains reduced ability to interact with
FT HSC20 and SDHB."
FT /evidence="ECO:0000269|PubMed:26749241"
FT CONFLICT 90
FT /note="C -> S (in Ref. 2; AAI37517/AAI37518)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 115 AA; 12806 MW; FD4933D1495979DE CRC64;
MSRHSRLQRQ VLSLYRDLLR AGRGKPGAEA RVRAEFRQHA GLPRSDVLRI EYLYRRGRRQ
LQLLRSGHAT AMGAFVRPRA PTGEPGGVGC QPDDGDSPRN PHDSTGAPET RPDGR
