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Protein

Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial

Gene

HADH

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Plays an essential role in the mitochondrial beta-oxidation of short chain fatty acids. Exerts it highest activity toward 3-hydroxybutyryl-CoA.

Catalytic activityi

(S)-3-hydroxyacyl-CoA + NAD+ = 3-oxoacyl-CoA + NADH.

Pathwayi: fatty acid beta-oxidation

This protein is involved in the pathway fatty acid beta-oxidation, which is part of Lipid metabolism.
View all proteins of this organism that are known to be involved in the pathway fatty acid beta-oxidation and in Lipid metabolism.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei57NAD2 Publications1
Binding sitei73Coenzyme A1
Binding sitei80Coenzyme A1
Binding sitei122NAD2 Publications1
Binding sitei127NAD2 Publications1
Binding sitei149Coenzyme A1
Binding sitei149NAD2 Publications1
Sitei170Important for catalytic activityCurated1
Binding sitei173NAD2 Publications1
Binding sitei305NAD2 Publications1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi34 – 39NAD2 Publications6

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Oxidoreductase

Keywords - Biological processi

Fatty acid metabolism, Lipid metabolism

Keywords - Ligandi

NAD

Enzyme and pathway databases

BioCyciMetaCyc:HS06563-MONOMER.
ZFISH:HS06563-MONOMER.
BRENDAi1.1.1.35. 2681.
ReactomeiR-HSA-77310. Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA.
R-HSA-77346. Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA.
R-HSA-77348. Beta oxidation of octanoyl-CoA to hexanoyl-CoA.
R-HSA-77350. Beta oxidation of hexanoyl-CoA to butanoyl-CoA.
R-HSA-77352. Beta oxidation of butanoyl-CoA to acetyl-CoA.
SABIO-RKQ16836.
UniPathwayiUPA00659.

Chemistry databases

SwissLipidsiSLP:000001250.

Names & Taxonomyi

Protein namesi
Recommended name:
Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial (EC:1.1.1.35)
Short name:
HCDH
Alternative name(s):
Medium and short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase
Short-chain 3-hydroxyacyl-CoA dehydrogenase
Gene namesi
Name:HADH
Synonyms:HAD, HADHSC, SCHAD
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 4

Organism-specific databases

HGNCiHGNC:4799. HADH.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Mitochondrion

Pathology & Biotechi

Involvement in diseasei

3-alpha-hydroxyacyl-CoA dehydrogenase deficiency (HADH deficiency)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA metabolic disorder with various clinical presentations including hypoglycemia, hepatoencephalopathy, myopathy or cardiomyopathy, and in some cases sudden death.
See also OMIM:231530
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_02407940A → T in HADH deficiency. 1 PublicationCorresponds to variant rs137853101dbSNPEnsembl.1
Natural variantiVAR_02408057D → E in HADH deficiency. 1 PublicationCorresponds to variant rs137853102dbSNPEnsembl.1
Familial hyperinsulinemic hypoglycemia 4 (HHF4)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionMost common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur. HHF4 should be easily recognizable by analysis of acylcarnitine species and that this disorder responds well to treatment with diazoxide. It provides the first 'experiment of nature' that links impaired fatty acid oxidation to hyperinsulinism and that provides support for the concept that a lipid signaling pathway is implicated in the control of insulin secretion.
See also OMIM:609975
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_024081258P → L in HHF4; loss of activity. 1 PublicationCorresponds to variant rs137853103dbSNPEnsembl.1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi3033.
MalaCardsiHADH.
MIMi231530. phenotype.
609975. phenotype.
OpenTargetsiENSG00000138796.
Orphaneti71212. Hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency.
PharmGKBiPA29173.

Polymorphism and mutation databases

BioMutaiHADH.
DMDMi311033442.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Transit peptidei1 – 12MitochondrionAdd BLAST12
ChainiPRO_000000740613 – 314Hydroxyacyl-coenzyme A dehydrogenase, mitochondrialAdd BLAST302

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei80N6-succinyllysineBy similarity1
Modified residuei81N6-acetyllysine; alternateBy similarity1
Modified residuei81N6-succinyllysine; alternateBy similarity1
Modified residuei87N6-acetyllysine; alternateBy similarity1
Modified residuei87N6-succinyllysine; alternateBy similarity1
Modified residuei125N6-acetyllysineBy similarity1
Modified residuei136N6-acetyllysine; alternateBy similarity1
Modified residuei136N6-succinyllysine; alternateBy similarity1
Modified residuei179N6-acetyllysineBy similarity1
Modified residuei185N6-acetyllysine; alternateCombined sources1
Modified residuei185N6-succinyllysine; alternateBy similarity1
Modified residuei192N6-acetyllysine; alternateBy similarity1
Modified residuei192N6-succinyllysine; alternateBy similarity1
Modified residuei202N6-acetyllysine; alternateCombined sources1
Modified residuei202N6-succinyllysine; alternateBy similarity1
Modified residuei206N6-succinyllysineBy similarity1
Modified residuei212N6-acetyllysine; alternateBy similarity1
Modified residuei212N6-succinyllysine; alternateBy similarity1
Modified residuei241N6-acetyllysine; alternateCombined sources1
Modified residuei241N6-succinyllysine; alternateBy similarity1
Modified residuei312N6-acetyllysine; alternateCombined sources1
Modified residuei312N6-succinyllysine; alternateBy similarity1

Post-translational modificationi

Succinylation at Lys-81, adjacent to a coenzyme A binding site. Desuccinylated by SIRT5 (By similarity).By similarity

Keywords - PTMi

Acetylation

Proteomic databases

EPDiQ16836.
MaxQBiQ16836.
PeptideAtlasiQ16836.
PRIDEiQ16836.
TopDownProteomicsiQ16836-1. [Q16836-1]

2D gel databases

REPRODUCTION-2DPAGEIPI00298406.
UCD-2DPAGEO00324.
Q16836.

PTM databases

iPTMnetiQ16836.
PhosphoSitePlusiQ16836.

Expressioni

Tissue specificityi

Expressed in liver, kidney, pancreas, heart and skeletal muscle.

Gene expression databases

BgeeiENSG00000138796.
CleanExiHS_HADH.
ExpressionAtlasiQ16836. baseline and differential.
GenevisibleiQ16836. HS.

Organism-specific databases

HPAiHPA039588.
HPA043888.

Interactioni

Subunit structurei

Homodimer.2 Publications

Protein-protein interaction databases

BioGridi109283. 23 interactors.
IntActiQ16836. 3 interactors.
MINTiMINT-5004681.

Structurei

Secondary structure

1314
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi1 – 11Combined sources11
Helixi14 – 22Combined sources9
Beta strandi29 – 33Combined sources5
Helixi37 – 48Combined sources12
Beta strandi52 – 56Combined sources5
Helixi60 – 79Combined sources20
Beta strandi82 – 84Combined sources3
Helixi86 – 98Combined sources13
Beta strandi100 – 104Combined sources5
Helixi106 – 109Combined sources4
Helixi110 – 112Combined sources3
Beta strandi114 – 118Combined sources5
Helixi124 – 134Combined sources11
Turni135 – 137Combined sources3
Beta strandi143 – 146Combined sources4
Beta strandi149 – 151Combined sources3
Helixi153 – 157Combined sources5
Helixi163 – 165Combined sources3
Beta strandi166 – 171Combined sources6
Turni175 – 177Combined sources3
Beta strandi180 – 184Combined sources5
Helixi191 – 203Combined sources13
Beta strandi207 – 211Combined sources5
Turni215 – 218Combined sources4
Helixi219 – 235Combined sources17
Helixi241 – 252Combined sources12
Helixi258 – 265Combined sources8
Helixi267 – 279Combined sources13
Turni280 – 283Combined sources4
Helixi285 – 287Combined sources3
Helixi291 – 298Combined sources8
Turni304 – 307Combined sources4
Beta strandi308 – 312Combined sources5

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1F0YX-ray1.80A/B13-314[»]
1F12X-ray2.40A/B13-314[»]
1F14X-ray2.30A/B13-314[»]
1F17X-ray2.30A/B13-314[»]
1IL0X-ray2.20A/B13-314[»]
1LSJX-ray2.50A/B13-314[»]
1LSOX-ray2.60A/B13-314[»]
1M75X-ray2.30A/B13-314[»]
1M76X-ray2.15A/B13-314[»]
2HDHX-ray2.20A/B24-314[»]
3HADX-ray2.00A/B13-314[»]
3RQSX-ray2.00A/B1-314[»]
ProteinModelPortaliQ16836.
SMRiQ16836.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ16836.

Family & Domainsi

Sequence similaritiesi

Keywords - Domaini

Transit peptide

Phylogenomic databases

GeneTreeiENSGT00720000108673.
HOGENOMiHOG000141498.
HOVERGENiHBG000832.
InParanoidiQ16836.
KOiK00022.
PhylomeDBiQ16836.
TreeFamiTF300886.

Family and domain databases

Gene3Di1.10.1040.10. 1 hit.
3.40.50.720. 1 hit.
InterProiIPR022694. 3-OHacyl-CoA_DH.
IPR006180. 3-OHacyl-CoA_DH_CS.
IPR006176. 3-OHacyl-CoA_DH_NAD-bd.
IPR006108. 3HC_DH_C.
IPR008927. 6-PGluconate_DH_C-like.
IPR013328. 6PGD_dom_2.
IPR016040. NAD(P)-bd_dom.
[Graphical view]
PfamiPF00725. 3HCDH. 1 hit.
PF02737. 3HCDH_N. 1 hit.
[Graphical view]
PIRSFiPIRSF000105. HCDH. 1 hit.
SUPFAMiSSF48179. SSF48179. 1 hit.
SSF51735. SSF51735. 1 hit.
PROSITEiPS00067. 3HCDH. 1 hit.
[Graphical view]

Sequences (3)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q16836-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MAFVTRQFMR SVSSSSTASA SAKKIIVKHV TVIGGGLMGA GIAQVAAATG
60 70 80 90 100
HTVVLVDQTE DILAKSKKGI EESLRKVAKK KFAENLKAGD EFVEKTLSTI
110 120 130 140 150
ATSTDAASVV HSTDLVVEAI VENLKVKNEL FKRLDKFAAE HTIFASNTSS
160 170 180 190 200
LQITSIANAT TRQDRFAGLH FFNPVPVMKL VEVIKTPMTS QKTFESLVDF
210 220 230 240 250
SKALGKHPVS CKDTPGFIVN RLLVPYLMEA IRLYERGDAS KEDIDTAMKL
260 270 280 290 300
GAGYPMGPFE LLDYVGLDTT KFIVDGWHEM DAENPLHQPS PSLNKLVAEN
310
KFGKKTGEGF YKYK
Length:314
Mass (Da):34,294
Last modified:November 2, 2010 - v3
Checksum:i0C6F7C01BBCE646A
GO
Isoform 2 (identifier: Q16836-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MGRAGLEAPPPPCGVTGTPGARGLQGRVGPRPQSLAFRGCLPRASSLPGSPRCRRRCHTM
     236-236: R → RDFQTCGDSNSGLGFSLK

Show »
Length:390
Mass (Da):42,140
Checksum:i3C20D80AAC4EB142
GO
Isoform 3 (identifier: Q16836-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     236-236: R → RDFQTCGDSNSGLGFSLK

Note: No experimental confirmation available.
Show »
Length:331
Mass (Da):36,051
Checksum:i11B5646AD077A666
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Isoform 2 (identifier: Q16836-2)
Sequence conflicti41L → P in AAB58153 (Ref. 2) Curated1
Sequence conflicti56R → H in AAB58153 (Ref. 2) Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_02407940A → T in HADH deficiency. 1 PublicationCorresponds to variant rs137853101dbSNPEnsembl.1
Natural variantiVAR_02408057D → E in HADH deficiency. 1 PublicationCorresponds to variant rs137853102dbSNPEnsembl.1
Natural variantiVAR_02676486L → P.4 PublicationsCorresponds to variant rs4956145dbSNPEnsembl.1
Natural variantiVAR_055701152Q → H.1 PublicationCorresponds to variant rs1051519dbSNPEnsembl.1
Natural variantiVAR_024081258P → L in HHF4; loss of activity. 1 PublicationCorresponds to variant rs137853103dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0165511M → MGRAGLEAPPPPCGVTGTPG ARGLQGRVGPRPQSLAFRGC LPRASSLPGSPRCRRRCHTM in isoform 2. 1 Publication1
Alternative sequenceiVSP_016552236R → RDFQTCGDSNSGLGFSLK in isoform 2 and isoform 3. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X96752 mRNA. Translation: CAA65528.1.
AF001902 mRNA. Translation: AAB54008.1.
AF001903 mRNA. Translation: AAB54009.1.
AF001904 Genomic DNA. Translation: AAB58153.1.
AF095703 Genomic DNA. Translation: AAD13581.1.
AC114733 Genomic DNA. Translation: AAY41050.1.
AC118062 Genomic DNA. No translation available.
BC000306 mRNA. Translation: AAH00306.1.
CCDSiCCDS3678.1. [Q16836-1]
CCDS54790.1. [Q16836-3]
PIRiJC4879.
RefSeqiNP_001171634.2. NM_001184705.2.
NP_005318.3. NM_005327.4.
UniGeneiHs.438289.

Genome annotation databases

EnsembliENST00000309522; ENSP00000312288; ENSG00000138796. [Q16836-1]
ENST00000603302; ENSP00000474560; ENSG00000138796. [Q16836-3]
GeneIDi3033.
KEGGihsa:3033.
UCSCiuc003hyq.4. human. [Q16836-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X96752 mRNA. Translation: CAA65528.1.
AF001902 mRNA. Translation: AAB54008.1.
AF001903 mRNA. Translation: AAB54009.1.
AF001904 Genomic DNA. Translation: AAB58153.1.
AF095703 Genomic DNA. Translation: AAD13581.1.
AC114733 Genomic DNA. Translation: AAY41050.1.
AC118062 Genomic DNA. No translation available.
BC000306 mRNA. Translation: AAH00306.1.
CCDSiCCDS3678.1. [Q16836-1]
CCDS54790.1. [Q16836-3]
PIRiJC4879.
RefSeqiNP_001171634.2. NM_001184705.2.
NP_005318.3. NM_005327.4.
UniGeneiHs.438289.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1F0YX-ray1.80A/B13-314[»]
1F12X-ray2.40A/B13-314[»]
1F14X-ray2.30A/B13-314[»]
1F17X-ray2.30A/B13-314[»]
1IL0X-ray2.20A/B13-314[»]
1LSJX-ray2.50A/B13-314[»]
1LSOX-ray2.60A/B13-314[»]
1M75X-ray2.30A/B13-314[»]
1M76X-ray2.15A/B13-314[»]
2HDHX-ray2.20A/B24-314[»]
3HADX-ray2.00A/B13-314[»]
3RQSX-ray2.00A/B1-314[»]
ProteinModelPortaliQ16836.
SMRiQ16836.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi109283. 23 interactors.
IntActiQ16836. 3 interactors.
MINTiMINT-5004681.

Chemistry databases

SwissLipidsiSLP:000001250.

PTM databases

iPTMnetiQ16836.
PhosphoSitePlusiQ16836.

Polymorphism and mutation databases

BioMutaiHADH.
DMDMi311033442.

2D gel databases

REPRODUCTION-2DPAGEIPI00298406.
UCD-2DPAGEO00324.
Q16836.

Proteomic databases

EPDiQ16836.
MaxQBiQ16836.
PeptideAtlasiQ16836.
PRIDEiQ16836.
TopDownProteomicsiQ16836-1. [Q16836-1]

Protocols and materials databases

DNASUi3033.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000309522; ENSP00000312288; ENSG00000138796. [Q16836-1]
ENST00000603302; ENSP00000474560; ENSG00000138796. [Q16836-3]
GeneIDi3033.
KEGGihsa:3033.
UCSCiuc003hyq.4. human. [Q16836-1]

Organism-specific databases

CTDi3033.
DisGeNETi3033.
GeneCardsiHADH.
GeneReviewsiHADH.
HGNCiHGNC:4799. HADH.
HPAiHPA039588.
HPA043888.
MalaCardsiHADH.
MIMi231530. phenotype.
601609. gene.
609975. phenotype.
neXtProtiNX_Q16836.
OpenTargetsiENSG00000138796.
Orphaneti71212. Hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency.
PharmGKBiPA29173.
GenAtlasiSearch...

Phylogenomic databases

GeneTreeiENSGT00720000108673.
HOGENOMiHOG000141498.
HOVERGENiHBG000832.
InParanoidiQ16836.
KOiK00022.
PhylomeDBiQ16836.
TreeFamiTF300886.

Enzyme and pathway databases

UniPathwayiUPA00659.
BioCyciMetaCyc:HS06563-MONOMER.
ZFISH:HS06563-MONOMER.
BRENDAi1.1.1.35. 2681.
ReactomeiR-HSA-77310. Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA.
R-HSA-77346. Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA.
R-HSA-77348. Beta oxidation of octanoyl-CoA to hexanoyl-CoA.
R-HSA-77350. Beta oxidation of hexanoyl-CoA to butanoyl-CoA.
R-HSA-77352. Beta oxidation of butanoyl-CoA to acetyl-CoA.
SABIO-RKQ16836.

Miscellaneous databases

ChiTaRSiHADH. human.
EvolutionaryTraceiQ16836.
GeneWikiiHydroxyacyl-Coenzyme_A_dehydrogenase.
GenomeRNAii3033.
PROiQ16836.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000138796.
CleanExiHS_HADH.
ExpressionAtlasiQ16836. baseline and differential.
GenevisibleiQ16836. HS.

Family and domain databases

Gene3Di1.10.1040.10. 1 hit.
3.40.50.720. 1 hit.
InterProiIPR022694. 3-OHacyl-CoA_DH.
IPR006180. 3-OHacyl-CoA_DH_CS.
IPR006176. 3-OHacyl-CoA_DH_NAD-bd.
IPR006108. 3HC_DH_C.
IPR008927. 6-PGluconate_DH_C-like.
IPR013328. 6PGD_dom_2.
IPR016040. NAD(P)-bd_dom.
[Graphical view]
PfamiPF00725. 3HCDH. 1 hit.
PF02737. 3HCDH_N. 1 hit.
[Graphical view]
PIRSFiPIRSF000105. HCDH. 1 hit.
SUPFAMiSSF48179. SSF48179. 1 hit.
SSF51735. SSF51735. 1 hit.
PROSITEiPS00067. 3HCDH. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiHCDH_HUMAN
AccessioniPrimary (citable) accession number: Q16836
Secondary accession number(s): J3KQ17
, O00324, O00397, O00753, Q4W5B4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 2, 2010
Last modified: November 2, 2016
This is version 185 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 4
    Human chromosome 4: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  6. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  7. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.