FAM63B

FAM63B is a protein which in humans is encoded by the gene FAM63B. This gene is highly expressed in humans. The FAM63B gene is also highly conserved throughout evolutionary history. The discovered function of FAM63B is an interaction with the kinesin-1 light chain and the transportation of vaccinia virus from the nucleus to the cell periphery.

Gene

Locus

FAM63B is located at 15q21.3-q22.1,[1] spanning 90,707 base pairs on chromosome 15.[2]

Alternative Names

The full name of FAM63B is family with sequence similarity 63, member B.[3] FAM63B is also listed by its alias, KIAA1164, in some publications.[4]

mRNA

Isoforms

The FAM63B gene encodes a primary transcript that can be alternatively spliced into 9 protein variants. FAM63B variant a is the most common isoform found in humans.[2]

VariantLength (amino acids)Exon CountMolecular Weight (kdal)Isoelectric Point
a621967.14.24
b620967.04.24
x16391069.24.40
x26381069.14.40
x36051065.24.41
x4587963.14.25
x5364638.04.50
x6351840.24.72
x7342839.14.45

[5]

Protein

Structure
Structure of FAM63B protein showing the domain of unknown function, bipartite tryptophan binding motif, hydrophobic stretchm, and KDEL signal.

Primary Structure

FAM63B is a member of the Pfam super family, and contains a domain of unknown function (DUF544) that is homologous within the protein family.[2] FAM63B protein variant an also contains a bipartite tryptophan binding motif from W476 to W533.[6] Variant a of the protein also contains a hydrophobic stretch of alanine from 567 to 574 and a mixed charge sequence from residue 598 to 617.[5] FAM63B protein may contain a signal sequence specifying return to the endoplasmic reticulum (KDEL) from residue 607 to 621 in variant a.

Secondary Structure

The secondary structure of FAM63B is a combination of coils, some α-helices, and few β-sheets.[5][7][8] The Phyre 2 program predicts α-helices in 23% of the protein, β-strands in 9% of the protein, and the remaining 59% of the protein as disordered.[7] The disordered regions coincide with the coiled regions predicted by other programs, and this results in the long stretch of coiled protein beginning at the N-terminus. According to the SOUSI program, there is a 16-amino acid-long span from residues 265 to 280 of FAM63B that could be a transmembrane sequence.[9] However, transmembrane sequences generally need to be at least 20 amino acids long in order to be stable in the membrane, so a transmembrane sequence is unlikely. Therefore, FAM63B is not fixed in the membrane of any organelle and is free to move through the cell and between organelles.

Tertiary Structure

Not much is known about the tertiary structure of FAM63B. A predicted folding is shown.

Predicted protein structure of FAM63B as determined by iTASSER.

Post-translational Modifications

Post-translational modifications of the FAM63B protein.[9]

Post-translational ModificationSite(s)Impact on Protein
AcetylationSer3Stability, localization, metabolism, apoptosis, ribosome recognition for synthesis
Lysine GlycationLys88, Lys251, Lys280, Lys282, Lys332, Lys393, Lys398, Lys454, Lys547Impaired function, changed characteristics
PhosphorylationSer7, Ser21, Ser25, Ser26, Ser62, Ser66, Ser68, Ser72, Ser90, Ser94, Ser111, Ser148, Ser153, Ser158, Ser160, Ser165, Ser170, Ser175, Ser188, Ser193, Ser233, Ser396, Ser440, Ser499, Ser541, Ser558, Ser587, Ser589, Ser590, Ser594, Ser597, Thr48, Thr255, Thr344, Thr453, Tyr505Conformation change, turn enzymatic activity on/off
Picornaviral CleavageGlu195, Gln535Cleavage of polyprotein, degradation
O-GlcNAcSer3, Ser21, Ser49, Ser62, Ser66, Ser68, Ser80, Ser152, Ser153, Ser158, Ser170, Ser499, Ser575, Ser587, Ser589, Ser590, Thr144, Thr576Nucleocytoplasmic location

Subcellular Location

FAM63B has predicted NES (nuclear export signals) at Val274 and Leu277.[10] Also, a NLS (nuclear localization signal) is predicted for FAM63B at RKRK at residue 599.[9] In agreement, Reinhardt's method for cytoplasmic/nuclear discrimination predicts FAM63B to be located in the nucleus with a reliability of 76.7%. The presence of both NLS and NES signals and O-GlcNAc post-translational modification of FAM63B supports the protein's location in both the nucleus and cytoplasm and the discovered protein function as a shuttle for vaccinia virus between the nucleus and the cell periphery.

Expression

Expression Level

FAM63B has moderately-high to high expression and is constitutively expressed. FAM63B is likely ubiquitously expressed in humans.[11]

Differential Expression

Expression of FAM63B is high in the embryonic stem cells and differentiated tissues but low or off in embryoid bodies and other progenitor cells, such as the multipotent mesenchymal stem cells. It is likely that FAM63B is expressed during pluripotency and unipotency but is not important for differentiation, as is occurring in embryoid bodies, mesenchymal stem cells, and other progenitor cells.

Differential FAM63B expression between human embryonic stem cells, hES-derived embryoid bodies, and hES-derived pancreatic cells.
Differential FAM63B expression between stromal cells from umbilical cord blood and mesenchymal stem cells.
Differential FAM63B expression between amniotic fluid kidney-progenitor podocytes and differentiated podocytes.
Profiles from NCBI UniGene show the expression of FAM63B in stem cell, embryoid body, and differentiated tissues.

Transcriptional Regulation

The promoter of FAM63B is GXP_5885, located on the positive strand of chromosome 15 from (58770692, 58771462) and is 711 base pairs long.[12]

Interacting Proteins

FAM63B is shown to interact with one protein, KLC-1.[13] KLC-1, kinesin light chain 1, is a protein which recruits kinesin-1 via its cargo binding light chain and contains a bipartite tryptophan binding motif.[13] This motif is present in a vaccinia virus integral membrane protein, A36, that is required for transport of the virus from the perinuclear space to the cell periphery.[13] In the absence of A36, proteins with a bipartite tryptophan binding motif can interact with the kinesin light chain, recruit KLC-1, and promote virus transport from the nucleus to the cytoplasm.[13]

Function

The discovered function of FAM63B protein is a transporter of vaccinia virus in the human genome. FAM63B contains a bipartite tryptophan binding motif between W476 and W533.[13] The motif also contains a Q residue at the +2 position, which was found to be a frequent occurrence in proteins that bind KLC-1 or KLC-2.[13] FAM63B is among proteins studied that can rescue virus transport to the cell periphery when expressed in A36-deficient cells, successfully replacing the cytoplasmic domain A36 of vaccinia.[13]

Clinical Significance

Pathology

The specific pathology of FAM63B is unknown.

Disease Association

FAM63B is part of four networks regulated by miRNA, three of which are linked to neuronal differentiation and dopaminergic gene expression.[14] These findings indicate that FAM63B could be used as a biomarker for the detection and treatment of schizophrenia.[14] Furthermore, aberrant methylation of FAM63B may play a role in the development of schizophrenia.[14] FAM63B has also been ranked 13 of 25 on a list of associated genes relevant to arthritis.[15]

Homology

Paralogs

FAM63B has one paralog, FAM63A, which is a gene of unknown function. FAM63A gene encodes a protein that is 469 amino acids long and 76% similar to FAM63B.[16]

Orthologs

FAM63B has been found in all multicellular and unicellular eukaryotes, including plants but excluding protists and fungi. The gene has also been found in archaea but not bacteria.[17]

Genus & speciesCommon NameDate of Divergence from Humans (MYA)Accession NumberSequence Length (amino acids)Sequence Similarity to Human Protein (%)Clade
Pan troglodytesChimpanzee6.2XP_510443.2621100Mammalia
Microtus ochrogasterPrairie vole90.1XP_005347720.159784Mammalia
Ursus maritimusPolar bear95XP_008704293.159197Mammalia
Acinonyx jubatusCheetah95XP_014926357.148896Mammalia
Pelodiscus sinensisGreen sea turtle320.5XP_014434471.140895Reptilia
Zonotrichia albicollisWhite-throated sparrow320.5XP_014123064.132691Aves
Columba liviaRock dove320.5XP_005511195.134091Aves
Chrysemys picta belliiWestern painted turtle320.5XP_008162326.156686Reptilia
Melopsittacus undulatusBudgerigar320.5XP_005145999.147286Aves
Xenopus tropicalisWestern clawed frog354.4XP_002937714.135487Amphibia
Latimeria chalumnaeWestern Indian Ocean coelacanth413.69XP_005998789.165283Sarcopterygii
Lepisosteus oculatusSpotted gar436.8XP_015198676.164282Actinopterygii
Hydra vulgarisHydra902XP_012556960.150765Hydrozoa
Octopus bimaculoidesCalifornia two-spot octopus903XP_014779548.198158Cephalopoda
Crassostrea gigasPacific oyster903XP_011440367.156971Bivalvia
Haemonchus contortusBarber's pole worm903CDJ97151.143755Secernentea
Trichoplax adhaerensTrichoplax936XP_002108532.130875Placozoa
Solanum pennelliiTomato1570.5XP_015085752.168665Angiosperms
Sesamum indicumSesame1570.5XP_011071984.173865Angiosperms
Thermoplasmatales archaeonBRNA14250WP_048164282.1106339Archaea

Distant Homologs

The most distant homolog of FAM63B is found in Thermoplasmatales archaeon, an archaea that diverged from the human gene 4.25 billion years ago.[17][18]

Homologous Domains

FAM63B is a member of the Pfam super family, and contains a domain of unknown function (DUF544) homologous within the protein family.[17] This region of the protein is highly conserved through FAM63B homologs, as is the bipartite tryptophan binding motif of FAM63B and the C-terminus signal sequence.

Phylogeny

The phylogenetic tree below shows a time calibration for the evolution of FAM63B.

The phylogenetic tree from TimeTree shows a time calibration for the evolution of FAM63B among humans (Has), prairie voles (Moc), polar bears (Uma), Western clawed frogs (Xtr), and Western Indian Ocean coelacanth (Latimeria chalumnae, Lch). The fish is the most diverged, followed by the amphibian, and the mammals, especially humans, are the least diverged. This is as expected in accordance with the evolutionary history of organisms on Earth, and FAM63B shows no great exception to the rule.

References
  1. "UCSC Genome Browser".
  2. "FAM63B family with sequence similarity 63 member B [Homo sapiens (human)] - Gene - NCBI". nih.gov.
  3. "Aliases for FAM63B Gene". GeneCards.
  4. https://www.genecards.org/cgi-bin/carddisp.pl?gene=FAM63B&keywords=FAM63B
  5. http://seqtool.sdsc.edu/CGI/BW.cgi#%5B%5D!
  6. Dodding, M. P., Mitter, R., Humphries, A. C., & Way, M. (2011). A kinesin-1 binding motif in vaccinia virus that is widespread throughout the human genome. The EMBO Journal, 30(22), 4523–4538. http://doi.org/10.1038/emboj.2011.326
  7. "Phyre 2 Results for Undefined". ic.ac.uk.
  8. "I-TASSER server for protein structure and function prediction". umich.edu.
  9. "ExPASy: SIB Bioinformatics Resource Portal - Categories". expasy.org.
  10. "5716AACA000019874EC1B1F0 expired". dtu.dk.
  11. "Family with sequence similarity 63, member B (FAM63B)". nih.gov.
  12. "Genomatix: Annotation & Analysis". genomatix.de.
  13. Dodding, M. P., Mitter, R., Humphries, A. C., & Way, M. (2011). A kinesin-1 binding motif in vaccinia virus that is widespread throughout the human genome. The EMBO Journal, 30(22), 4523–4538. http://doi.org/10.1038/emboj.2011.326
  14. Aberg, K. A., et al. (2014). Methylome-Wide Association Study of Schizophrenia. JAMA Psychiatry, 71(3), 255–264. http://doi.org/10.1001/jamapsychiatry.2013.3730
  15. Li, C., et al. (2008). A systematic method for mapping multiple loci: An application to construct a genetic network for rheumatoid arthritis. Gene, 408(1–2), 104–111. http://doi.org/10.1016/j.gene.2007.10.028
  16. "FAM63A family with sequence similarity 63 member A [Homo sapiens (human)] - Gene - NCBI". nih.gov.
  17. "BLAST: Basic Local Alignment Search Tool". nih.gov.
  18. "TimeTree". timetree.org.
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