Q9H2C0 (GAN_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Gigaxonin

Alternative name(s):
Kelch-like protein 16

Gene names

Name:	GAN
Synonyms:	GAN1, KLHL16

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	597 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Probable cytoskeletal component that directly or indirectly plays an important role in neurofilament architecture. May act as a substrate-specific adapter of an E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Controls degradation of TBCB. Controls degradation of MAP1B and MAP1S, and is critical for neuronal maintenance and survival. Ref.3 Ref.5 Ref.6 Ref.7
Pathway	Protein modification; protein ubiquitination.
Subunit structure	Interacts with TBCB. Interacts with CUL3. Part of a complex that contains CUL3, RBX1 and GAN. Interacts (via BTB domain) with UBA1. Interacts (via Kelch domains) with MAP1B (via C-terminus) and MAP1S (via C-terminus). Ref.3 Ref.4 Ref.5 Ref.6 Ref.7
Subcellular location	Cytoplasm. Cytoplasm › cytoskeleton Ref.3 Ref.8.
Tissue specificity	Expressed in brain, heart and muscle. Ref.3
Post-translational modification	Ubiquitinated by E3 ubiquitin ligase complex formed by CUL3 and RBX1 and probably targeted for proteasome-independent degradation. Ref.6
Involvement in disease	Giant axonal neuropathy (GAN) [MIM:256850]: Severe autosomal recessive sensorimotor neuropathy affecting both the peripheral nerves and the central nervous system. It is characterized by neurofilament accumulation, leading to segmental distention of axons. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.1 Ref.5 Ref.11 Ref.13 Ref.14 Ref.15
Sequence similarities	Contains 1 BACK (BTB/Kelch associated) domain. Contains 1 BTB (POZ) domain. Contains 6 Kelch repeats.

Ontologies

Keywords
Biological process	Ubl conjugation pathway
Cellular component	Cytoplasm Cytoskeleton
Coding sequence diversity	Polymorphism
Disease	Disease mutation Neurodegeneration
Domain	Kelch repeat Repeat
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cell death Inferred from electronic annotation. Source: UniProtKB-KW protein ubiquitination Inferred from direct assay Ref.6. Source: UniProtKB
Cellular_component	Cul3-RING ubiquitin ligase complex Inferred from direct assay Ref.6. Source: UniProtKB cytoplasm Inferred from direct assay Ref.8. Source: UniProtKB neurofilament Non-traceable author statement. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
MAP1B	P46821	3	EBI-764342,EBI-764611
TBCB	Q99426	3	EBI-764342,EBI-764356
UBA1	P22314	5	EBI-764342,EBI-709688

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 597

597

Gigaxonin

PRO_0000119070

Regions

Domain

30 – 99

70

BTB

Domain

134 – 236

103

BACK

Repeat

274 – 326

53

Kelch 1

Repeat

327 – 374

48

Kelch 2

Repeat

376 – 421

46

Kelch 3

Repeat

422 – 468

47

Kelch 4

Repeat

470 – 522

53

Kelch 5

Repeat

528 – 574

47

Kelch 6

Amino acid modifications

Modified residue

8

1

Phosphoserine By similarity

Modified residue

471

1

Phosphotyrosine By similarity

Natural variations

Natural variant

15

1

R → S in GAN; no effect on binding to TBCB. Ref.1 Ref.5

VAR_010759

Natural variant

51

1

A → P in GAN. Ref.14

VAR_054113

Natural variant

52

1

S → G in GAN. Ref.1

VAR_010760

Natural variant

79

1

S → L in GAN. Ref.1

VAR_010761

Natural variant

82

1

V → F in GAN; no effect on binding to TBCB. Ref.1 Ref.5

VAR_010762

Natural variant

86

1

I → F in GAN. Ref.13

VAR_015680

Natural variant

89

1

Y → C in GAN. Ref.15

VAR_054114

Natural variant

138

1

R → H in GAN. Ref.1

VAR_010763

Natural variant

195

1

V → F in GAN. Ref.15

VAR_054115

Natural variant

269

1

R → Q in GAN. Ref.1 Ref.13

VAR_010764

Natural variant

309

1

L → R in GAN. Ref.1

VAR_010765

Natural variant

315

1

P → L in GAN. Ref.14

VAR_054116

Natural variant

368

1

G → R in GAN. Ref.13 Ref.15

VAR_015681

Natural variant

423

1

I → T in GAN. Ref.11 Ref.15

VAR_015560

Natural variant

474

1

G → R in GAN. Ref.15

VAR_054117

Natural variant

486

1

E → K in GAN. Ref.1

VAR_010757

Natural variant

545

1

R → C in GAN; complete loss of binding to TBCB. Ref.1 Ref.5

VAR_010766

Natural variant

545

1

R → H in GAN. Ref.15

VAR_054118

Natural variant

570

1

C → Y in GAN. Ref.1

VAR_010767

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

597

Helix Strand Turn

Details...

Helix

12 – 22

11

Beta strand

32 – 36

5

Beta strand

39 – 43

5

Helix

45 – 51

7

Helix

53 – 61

9

Beta strand

72 – 74

3

Helix

80 – 90

11

Turn

99 – 101

3

Helix

102 – 111

10

Helix

115 – 122

8

Helix

135 – 143

9

Helix

150 – 164

15

Helix

214 – 224

11

Helix

230 – 237

8

Sequences

	Sequence		Length	Mass (Da)
	Q9H2C0 [UniParc]. Last modified March 1, 2001. Version 1. Checksum: 4B6ECFA6849880C7	FASTA	597	67,638
	10 20 30 40 50 60 MAEGSAVSDP QHAARLLRAL SSFREESRFC DAHLVLDGEE IPVQKNILAA ASPYIRTKLN 70 80 90 100 110 120 YNPPKDDGST YKIELEGISV MVMREILDYI FSGQIRLNED TIQDVVQAAD LLLLTDLKTL 130 140 150 160 170 180 CCEFLEGCIA AENCIGIRDF ALHYCLHHVH YLATEYLETH FRDVSSTEEF LELSPQKLKE 190 200 210 220 230 240 VISLEKLNVG NERYVFEAVI RWIAHDTEIR KVHMKDVMSA LWVSGLDSSY LREQMLNEPL 250 260 270 280 290 300 VREIVKECSN IPLSQPQQGE AMLANFKPRG YSECIVTVGG EERVSRKPTA AMRCMCPLYD 310 320 330 340 350 360 PNRQLWIELA PLSMPRINHG VLSAEGFLFV FGGQDENKQT LSSGEKYDPD ANTWTALPPM 370 380 390 400 410 420 NEARHNFGIV EIDGMLYILG GEDGEKELIS MECYDIYSKT WTKQPDLTMV RKIGCYAAMK 430 440 450 460 470 480 KKIYAMGGGS YGKLFESVEC YDPRTQQWTA ICPLKERRFG AVACGVAMEL YVFGGVRSRE 490 500 510 520 530 540 DAQGSEMVTC KSEFYHDEFK RWIYLNDQNL CIPASSSFVY GAVPIGASIY VIGDLDTGTN 550 560 570 580 590 YDYVREFKRS TGTWHHTKPL LPSDLRRTGC AALRIANCKL FRLQLQQGLF RIRVHSP

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy." Bomont P., Cavalier L., Blondeau F., Ben-Hamida C., Belal S., Tazir M., Demir E., Topaloglu H., Korinthenberg R., Tueysuez B., Landrieu P., Hentati F., Koenig M. Nat. Genet. 26:370-374(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANTS GAN SER-15; GLY-52; LEU-79; PHE-82; HIS-138; GLN-269; ARG-309; LYS-486; CYS-545 AND TYR-570. Tissue: Brain.
[2]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Placenta.
[3]	"Microtubule-associated protein 1B: a neuronal binding partner for gigaxonin." Ding J., Liu J.-J., Kowal A.S., Nardine T., Bhattacharya P., Lee A., Yang Y. J. Cell Biol. 158:427-433(2002) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH MAP1B, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[4]	"Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubiquitin ligases." Furukawa M., He Y.J., Borchers C., Xiong Y. Nat. Cell Biol. 5:1001-1007(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CUL3.
[5]	"Gigaxonin interacts with tubulin folding cofactor B and controls its degradation through the ubiquitin-proteasome pathway." Wang W., Ding J., Allen E., Zhu P., Zhang L., Vogel H., Yang Y. Curr. Biol. 15:2050-2055(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH TBCB, CHARACTERIZATION OF VARIANTS GAN SER-15; PHE-82 AND CYS-545.
[6]	"Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway." Zhang D.D., Lo S.C., Sun Z., Habib G.M., Lieberman M.W., Hannink M. J. Biol. Chem. 280:30091-30099(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, IDENTIFICATION IN A COMPLEX WITH CUL3 AND RBX1, UBIQUITINATION.
[7]	"Gigaxonin-controlled degradation of MAP1B light chain is critical to neuronal survival." Allen E., Ding J., Wang W., Pramanik S., Chou J., Yau V., Yang Y. Nature 438:224-228(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH UBA1 AND MAP1B.
[8]	"Ectodermal-neural cortex 1 down-regulates Nrf2 at the translational level." Wang X.J., Zhang D.D. PLoS ONE 4:E5492-E5492(2009) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION.
[9]	"Structures of SPOP-substrate complexes: insights into molecular architectures of BTB-Cul3 ubiquitin ligases." Zhuang M., Calabrese M.F., Liu J., Waddell M.B., Nourse A., Hammel M., Miller D.J., Walden H., Duda D.M., Seyedin S.N., Hoggard T., Harper J.W., White K.P., Schulman B.A. Mol. Cell 36:39-50(2009) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 1-254.
[10]	"Structure of the BTB (tramtrack and bric a brac) domain of human gigaxonin." Structural genomics consortium (SGC) Submitted (JUL-2011) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 6-126.
[11]	"Giant axonal neuropathy (GAN): case report and two novel mutations in the gigaxonin gene." Kuhlenbaumer G., Young P., Oberwittler C., Hunermund G., Schirmacher A., Domschke K., Ringelstein B., Stogbauer F. Neurology 58:1273-1276(2002) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT GAN THR-423.
[12]	Erratum Kuhlenbaumer G., Young P., Oberwittler C., Hunermund G., Schirmacher A., Domschke K., Ringelstein B., Stogbauer F. Neurology 58:1444-1444(2002)
[13]	"Identification of seven novel mutations in the GAN gene." Bomont P., Ioos C., Yalcinkaya C., Korinthenberg R., Vallat J.-M., Assami S., Munnich A., Chabrol B., Kurlemann G., Tazir M., Koenig M. Hum. Mutat. 21:446-446(2003) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS GAN PHE-86; GLN-269 AND ARG-368.
[14]	"New mutations, genotype phenotype studies and manifesting carriers in giant axonal neuropathy." Houlden H., Groves M., Miedzybrodzka Z., Roper H., Willis T., Winer J., Cole G., Reilly M.M. J. Neurol. Neurosurg. Psych. 78:1267-1270(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS GAN PRO-51 AND LEU-315.
[15]	"Genotype-phenotype analysis in patients with giant axonal neuropathy (GAN)." Koop O., Schirmacher A., Nelis E., Timmerman V., De Jonghe P., Ringelstein B., Rasic V.M., Evrard P., Gaertner J., Claeys K.G., Appenzeller S., Rautenstrauss B., Huehne K., Ramos-Arroyo M.A., Woerle H., Moilanen J.S., Hammans S., Kuhlenbaeumer G. Neuromuscul. Disord. 17:624-630(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS GAN CYS-89; PHE-195; ARG-368; THR-423; ARG-474 AND HIS-545.
+	Additional computationally mapped references.

Web resources

Inherited peripheral neuropathies mutation db

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF291673 mRNA. Translation: AAG35311.1.
BC044840 mRNA. Translation: AAH44840.1.

IPI

IPI00022758.

RefSeq

NP_071324.1. NM_022041.3.

UniGene

Hs.112569.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2PPI	X-ray	2.40	A	6-126	[»]
3HVE	X-ray	2.80	A/B	1-254	[»]

ProteinModelPortal

Q9H2C0.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9H2C0. 6 interactions.

MINT

MINT-243055.

STRING

9606.ENSP00000248272.

PTM databases

PhosphoSite

Q9H2C0.

Polymorphism databases

DMDM

13626745.

Proteomic databases

PaxDb

Q9H2C0.

PRIDE

Q9H2C0.

Protocols and materials databases

DNASU

8139.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000248272; ENSP00000248272; ENSG00000127688.

GeneID

8139.

KEGG

hsa:8139.

UCSC

uc002fgo.3. human.

Organism-specific databases

CTD

8139.

GeneCards

GC16P081348.

HGNC

HGNC:4137. GAN.

HPA

CAB011825.

MIM

256850. phenotype.
605379. gene.

neXtProt

NX_Q9H2C0.

Orphanet

643. Giant axonal neuropathy.

PharmGKB

PA28550.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG274392.

HOGENOM

HOG000290709.

HOVERGEN

HBG005802.

InParanoid

Q9H2C0.

KO

K10453.

OMA

DGERELI.

OrthoDB

EOG40P46B.

PhylomeDB

Q9H2C0.

Enzyme and pathway databases

Reactome

REACT_6900. Immune System.

UniPathway

UPA00143.

Gene expression databases

Bgee

Q9H2C0.

CleanEx

HS_GAN.

Genevestigator

Q9H2C0.

GermOnline

ENSG00000127688. Homo sapiens.

Family and domain databases

Gene3D

2.120.10.80. 1 hit.
3.30.710.10. 1 hit.

InterPro

IPR011705. BACK.
IPR000210. BTB/POZ-like.
IPR011333. BTB/POZ_fold.
IPR013069. BTB_POZ.
IPR017096. Kelch-like_gigaxonin.
IPR015915. Kelch-typ_b-propeller.
IPR006652. Kelch_1.
[Graphical view]

Pfam

PF07707. BACK. 1 hit.
PF00651. BTB. 1 hit.
PF01344. Kelch_1. 3 hits.
[Graphical view]

PIRSF

PIRSF037037. Kelch-like_protein_gigaxonin. 1 hit.

SMART

SM00875. BACK. 1 hit.
SM00225. BTB. 1 hit.
SM00612. Kelch. 5 hits.
[Graphical view]

SUPFAM

SSF54695. BTB/POZ_fold. 1 hit.

PROSITE

PS50097. BTB. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

GAN. human.

EvolutionaryTrace

Q9H2C0.

GenomeRNAi

8139.

NextBio

30807.

SOURCE

Search...

Entry information

Entry name

GAN_HUMAN

Accession

Primary (citable) accession number: Q9H2C0

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 27, 2001
Last sequence update:	March 1, 2001
Last modified:	May 1, 2013
This is version 124 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.