In humans, the FHAD1 gene is located on chromosome 1 (1p36.21) and the genomic sequence is on the plus strand starting from 15236559 bp and ending at 15400283 bp.[1] There are 3 main genes around FHAD1, out of which 2 encode proteins with known functions. Two genes, EFHD2 and Chymotrypsin-C (CTRC) lie downstream of FHAD1 on the plus strand.[1]TMEM51 lies upstream of FHAD1.[1]
FHAD1 is 163,682 bases long and contains 43 exons.
Common Aliases
FHAD1 has 4 aliases, Forkhead associated phosphopeptide binding domain 1, Forkhead-associated (FHA) phosphopeptide binding domain 1, FHA Domain-Containing Protein 1, and KIAA1937.[2]
mRNA
The mRNA transcript of FHAD1 5138 bp long. The gene has 30 isoforms based on NCBI gene data.
The FHAD 1 protein is 1412 aa long, weighs 16.2 kDa and has an isoelectric point of 6.52.[3] It has 3 isoforms, namely 1, 3 and 4, but only isoform 1 is supported by experimental evidence. It consists of 1 glutamic acid rich region and 1 proline rich region.
Domains and Motifs
Forehead-associated domain
The FHA domain extends from 18 - 84 aa in the protein. It can recognize and bind to phosphorylation sites, specifically pSer, pThr and pTyr. The exact mechanism and function of this domain still being studied, but it is found in proteins performing many different functions, mainly DNA repair and transduction.[4]
FHAD1 contains one Smc (Structural maintenance of chromosomes) region from 275 - 1401 aa. This region encodes Smc proteins that are involved in cell cycle control, cell division and chromosome separation.[5]
TMPIT-like protein, pfam07851
This region extends from 394 - 494 aa in FHAD1. The proteins encoded by the TMPIT proteins are predicted to be transmembrane proteins.[6] However, there is lack of literature to support this.
DUF342
This domain extends from 694 - 777 aa in FHAD1. It encodes a protein from a family of bacterial proteins with no known function.[7]
FHAD1 contains the forkhead-associated domain that consists of beta sheets. Based on structure prediction softwares, the rest of the protein consists of alpha helices and random coils. Overall, FHAD1 has a coiled coil structure as shown in the figure.
Post-translational modifications
FHAD1 is predicted to undergo multiple different types of post-translational modifications based on prediction softwares.
Phosphorylation: The protein was predicted to have a large number of phosphorylation sites, at least more than 100.
Glycation: Multiple lysine residues of FHAD1 were predicted for glycation of their ε amino groups.
SUMOylation: 4 SUMOylation consensus sequences and 3 interaction sites were predicted on FHAD1.
O-GlcNAc sites: 6 sites for O-GlcNAc glycosylation were predicted on FHAD1. Research has shown that this specific type of glycosylation is most abundant in nucleocytoplasmic proteins.[8]
FHAD1 has been predicted to be a nuclear protein with 94.1% reliability. It also contains possible nuclear localization signal sequences between 1100 - 1107 aa. Two pat4 and one pat7 sequences were predicted. Pat4 and pat7 are consensus sequences consisting of clusters of lysine or arginine residues.
FHAD1 has a promoter that extends from 15246234 – 15247380 bp and is 1147 bp long. It includes an initial part of the 5' UTR of FHAD1. Some transcription factors predicted to bind to this promoter are:
MAX binding protein - This protein is likely a transcriptional repressor from the E-box binding factors family[10]
Kaiso - This transcriptional regulator is encoded by the ZBTB33 gene and is involved in response to DNA damage by interacting with p53[12]
LYL1-E12 - This transcriptional factor is a dimer of two proteins, LYL1 and E12, where E12 is an E-box binding protein. LYL1 is also involved in some leukemias and is a possible oncogenic factor[13].
Nur 77 - This protein is also known as NGFIB (Nerve growth factor IB) and belongs to a family of nuclear receptors. It is involved in apoptosis and cell growth pathways.[14]
In the 5' UTR and 3' UTR of FHAD1, multiple stem loops are predicted to form .
Function
FHAD1 can be involved in transcriptional regulation through interaction with other transcriptional regulators.
Protein interactions
FHAD1 was found to be a binding partner for GTF2IRD1 (GTF2I repeat domain containing protein 1) via a yeast 2 hybrid screen[15]. GTF2I is a gene that encodes the general transcription factor II-1. This specific study showed that GTF2IRD1 is a nuclear protein that is involved transcriptional regulation through chromatin modification. The fact that it exists in the nucleus and was found in neuronal cells correlates with the localization and functional data for FHAD1. Additionally, FHAD1 and GTF2IRD1 interacted through RD2 (repeat domain 2) of GTF2IRD1. RD2 has shown some level of DNA binding activity.
FHAD1 was found to interact (colocalization) with14-3-3 protein epsilon via cosedimentation. This protein binds to a number of binding partners, mostly by recognizing phosphothreonine or phosphoserine motifs[16].
↑Weng JH, Hsieh YC, Huang CC, Wei TY, Lim LH, Chen YH, Ho MR, Wang I, Huang KF, Chen CJ, Tsai MD (October 2015). "Uncovering the Mechanism of Forkhead-Associated Domain-Mediated TIFA Oligomerization That Plays a Central Role in Immune Responses". Biochemistry. 54 (40): 6219–29. doi:10.1021/acs.biochem.5b00500. ISSN0006-2960. PMID26389808.
