BTBD16

BTB Domain-containing 16 (BTBD16) is a protein which in humans is encoded by the BTBD16 gene. The primary alias is chromosome 10 open reading frame 87 (c10orf87), but this is less commonly used than BTBD16.

In the human genome, BTBD16 is located on the plus strand of chromosome 10 at 10q26.13.^[5] The sequence spans 66,682 base pairs and contains 16 exons.^[6] There are two main regions within the BTBD16 protein: the Broad-Complex, Tramtrack, and Bric a brac (BTB) and poxvirus and zinc finger (POZ) domain (BTB/POZ) and the BTB and C-terminal Kelch (BACK) domain.

BTBD16 is expressed at low levels across all tissues in the human body. Highest expression is within the brain, spinal cord, and liver, though these are each still expressed below the 50th percentile compared to other human proteins.^[7] There is also marginally higher expression within the urinary bladder and testes at 4.5 RPKM and 2.5 RPKM, respectively, though at lower confidence.^[8]

There are 7 known splice variants in humans, with transcript variant 1 having the longest nucleotide length at 1859 nucleotides and encoding the longest isoform, protein isoform A, at 507 amino acids.^[9]

There are few noted regulation sites within transcript variant 1:^[10]

• upstream in-frame stop codon ("taa" at location 244–246)
• poly-A signal sequence ("aataaa" at location 1839–1844)
• poly-A site ("a" at location 1859)

The 5' untranslated region (UTR) creates a Y-like shape and likely has 9 sites of binding for RNA Binding Motif Protein, X-chromosome (RBMX).^[12] This gene is implicated in regulating tissue-specific gene expression.

BTBD16 protein isoform A contains 507 amino acids and has a molecular weight of approximately 58.5 kDa.^[13] There is a marginally higher composition of phenylalanine (F) within this protein than the average human protein.^[14] Otherwise, there are no notable charged domains or transmembrane segments. It has an isoelectric point of 9.3, meaning it will be positively charged in the general cell environment.^[15]

BTBD16 protein isoform A has a nuclear localization sequence (NLS) of PKKTKEK, meaning it can localize within the nucleus of the cell.^[16] It is also predicted to localize within the cytosol and/or the mitochondria, all of which are consistent with predicted protein interactions.

There are 20 alpha helices and 15 beta strands within the structure of this protein.^[17] Most models for BTBD16 are based on Kelch-like proteins and BTB domain-containing regions and Kelch domains within proteins that are more studied than this one.^[18] This further confirms the presences of the BTB and BACK domains within the BTBD16 gene and protein.

There are few high scoring post-translational modification sites within the main isoform of BTBD16:^[19]

• LIG_FAT_LD1: part of the paxillin leucine-rich repeat motif family; recognized by focal adhesion proteins involved in regulation of the cytoskeleton.
• LIG_PAM2_1: peptide ligand binding motif; binds to domain found in polyA-binding proteins and E3 ubiquitin ligases.
• DOC_MAPK_FxFP_2 : helps regulate the mitogen-activated protein kinase pathway (MAPK), transferring cell signals from external stimuli to internal responses.

There are 22 high scoring protein kinase C (PKC) sites within BTBD16 as well.^[20]

BTBD16 may interact with multiple different proteins. It is co-expressed with both pleckstrin homology domain-containing family A member 1 (PLEKHA1) and transforming acidic coiled-coil-containing protein 16 (TACC2).^[21] These two genes are directly down and upstream of BTBD16, respectively.^[6]

Proteins found to interact with BTBD16 through two-hybrid experiments are PAX-interacting protein 1 (PAXIP1) and rhophilin associated tail protein 1 (ROPN1).^[22]

Other proteins mentioned in papers alongside BTBD16 are coiled-coil domain containing 191 (CCDC191), DPY19L3, age-related maculopathy susceptibility 2 (ARMS2), and NADH dehydrogenase complex I assembly factor 6 (NDUFAF6).^[21]

BTBD16 has been found in species as far back as cartilaginous fishes, but not jawless fish, invertebrates, or bacteria.^[23]

Various studies, mainly Genome Wide Association Studies (GWAS), note variants in the BTBD16 in association with type 2 diabetes,^[24][25] bipolar disorder,^[26][27] Alzheimer's disease,^[24][28] and multiple cancers like bladder^[29] and breast.^[30]

There are no known malignant variations within the BTBD16 gene specifically that are of clinical significance. One single nucleotide polymorphism (SNP) has been labeled as a variant of unknown significance (VUS) in correlation with malignant prostate tumor.^[31] This is a missense mutation in proline 29 that becomes a serine.