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CFAP97D2

Predicted three-dimensional structure of CFAP97D2 from I-TASSER

Cilia- and flagella-associated protein 97 domain-containing 2 (CFAP97D2) also known as KIAA1430

(previous name) is a protein encoded by the CFAP97D2 gene. It plays a vital role in the nucleus.

Gene

CFAP97D2 gene is 50,003bp long. It is located at 114173082bp to 114223032bp on human chromosome 13 and contains 8 exons. It belongs to the cilia-and flagella-associated 97 (CFAP97) gene family, which has three genes: CFAP97, CFAP97D1, and CFAP97D2.

Transcripts

There are three known transcript variants: transcript variant X1, transcript variant 1, and transcript variant 2.

Transcript variants of CFAP97D2

Transcript variant	Accession number	Length	Encoded protein	Protein length
Transcript variant X1	XM_017020910	5446bp	isoform X1 (XP_016876399)	166aa
Transcript variant 1	NM_001395230	952bp	isoform 1 (NP_001382159)	99aa
Transcript variant 2	NM_001395229	949bp	isoform 2 (NP_001382158)	98aa

Transcript expression

CFAP97D2 transcripts have a low abundance and are found to be expressed in a wide array of organs enriched with connective tissues, such as the brain, testes, ovary, fallopian tube, white blood cells, bone marrows.

In immune cells, CFAP97D2 is specifically enriched in naive CD8 T cells. This specificity suggests its critical role in the immune system contributing to the complex network of cells.

Proteins

There are three known CFAP97D2 protein isoforms: isoform X1, isoform 1, and isoform 2.

The longest protein isoform X1 consists of 166 amino acids, with a molecular weight of 19kDa and an isoelectric point of 10.4. There is a relatively high content of lysine, phenylalanine, and leucine in CFAP97D2, resulting in a relatively high total charge.

Domains and motifs

CFAP97D2 has a domain named “KIAA1430” that spans residues 27 to 111. This domain is highly conserved across vertebrates, invertebrates, and fungi, and it is also considered to be specifically related to motile cilia.

An analysis through PSORT II found a conserved mitochondrial processing peptidase cleavage site is found in CFAP97D2 at residue 16. And a conserved nuclear localization signal is found at residue 27. This indicates the vital role of CFAP97D2 in the nucleus. Additionally, human CFAP97D2 is predicted to have a unique leucine-zipper-pattern of 63 DNA binding motif at residue 37, which can help distinguish nuclear proteins.

Structure

The secondary structure of CFAP97D2 is highly conserved among species, and most are composed of alpha-helices with beta-sheets and coiled connected. The KIAA1430 domain consists of two helices and connected coils. There is a coiled coil conserved in human CFAP97D2 from residues 48 to 109.

There is no disulfide bond and transmembrane domains found in CFAP97D2.

Subcellular localization

CFAP97D2 has a high likelihood to localize in mitochondria and nucleus, and to be soluble in the cytoplasm.

Regulation

Gene level regulation

Two promoters are found in the CFAP97D2 gene via Genomatix. Promoter A (GXP_6735018) encodes for transcript X1 while promoter B (GXP_7530125) encodes for transcripts 1 and 2. Several different transcription factors within promoter A regulate the expression of the CFAP97D2 gene (function found on Genomatix promoter annotation).

Conserved regulatory transcription factors in promoter

Transcription factors	Full name	Function
MYT1	MYT1 C2HC zinc finger protein	regulate the expression in the brain and bone marrows (immune system).
PAR	PAR/bZIP family	regulate the expression in the brain and bone marrows (immune system).
Paralog Hox	Paralog hox genes 1-8 from the four hox clusters A, B, C, D	function in adipose tissue may also lead to high expressions in the fatty tissues of the reproductive system
cAMP	cAMP-responsive element binding proteins	function in adipose tissue may also lead to high expressions in the fatty tissues of the reproductive system

Post-translational modifications

There are sixteen residues along CFAP97D2 protein that are likely phosphorylation modification sites, and eleven internal lysines are likely acetylation modification sites. These two types of sites are highly conserved in the KIAA1430 domain across species. There are also three SUMOylation consensus sites overlapping with acetylation sites. Each of these post-translational modifications is expected to have an effect on the protein. The phosphorylation sites can reduce the isoelectric point of CFAP97D2 to 9.77 if all conserved sites were modified. Acetylation of internal lysines may influence the intermolecular interactions eventual degradation of CFAP97D2. SUMOylation sites are residues that SUMO (small ubiquitin-like modifier) proteins can attach to CFAP97D2 and affect its nuclear-cytosolic transport and transcriptional regulation.

Homology and evolution

CFAP97D2 is determined to be a homolog of uncharacterized protein C17orf105, and has orthologs widely among invertebrates, vertebrates, and fungi. So far, no existing paralog is detected.

Seq #	Group	Genus and species	Common name	Taxonomic group	Date of divergence from the human lineage (MYA)	Accession number	Sequence length	Query cover	Sequence identity to human protein	Sequence similarity to human protein
1	Mammals	Homo sapiens	Human	Hominin	0	XP_016876399	166	100%	100.00%	100.0%
2		Mus musculus	House mouse	Rodentia	90	NP_001094989.1	96	57%	62.50%	44.0%
3		Phyllostomus discolor*	Pale spear-nosed bat	Chiroptera	96	KAF6083800	169	58%	68.04%	58.6%
4		Orycteropus afer afer	Aardvark	Tubulidentata	105	XP_042637093	97	57%	70.83%	51.8%
5	Birds	Egretta garzetta	Little egret	Pelecaniformes	312	XP_009637256	186	70%	54.24%	53.3%
6		Tauraco erythrolophus	Red-crested turaco	Musophagiformes	312	XP_009987599	162	70%	53.39%	53.3%
7		Antrostomus carolinensis	Chuck-will's-widow	Caprimulgiformes	312	XP_010175828	157	70%	46.61%	50.3%
8	Reptiles	Pogona vitticeps	Central bearded dragon	Squamata	312	XP_020639639	116	69%	53.45%	53.3%
9		Chelonia mydas	Green sea turtle	Testudines	312	XP_007063899	118	70%	52.54%	55.1%
10	Amphibians	Ranitomeya imitator	Mimic poison frog	Anura	351.8	CAF5206259	92	55%	61.96%	43.4%
11		Bufo bufo	Common toad	Anura	351.8	XP_040281015	111	66%	60.36%	53.9%
12		Rhinatrema bivittatum	Rhinatrema	Gymnophiona	351.8	XP_029460476	111	66%	56.76%	53.9%
13		Xenopus tropicalis	Western clawed frog	Anura	351.8	XP_012812129	118	70%	49.15%	53.3%
14	Bony Fish	Lepisosteus oculatus	Spotted gar	Lepisosteiformes	435	XP_006639009	115	68%	50.43%	51.5%
15		Scyliorhinus torazame	Cloudy catshark	Carcharhiniformes	473	GCB80112	116	69%	48.28%	49.1%
16	Invetebrates	Styela clava	Stalked sea squirt	Stolidobranchia	676	XP_039250546.1	111	66%	55.75%	50.3%
17		Apostichopus japonicus	Japanese spiky sea cucumber	Synallactida	684	PIK62955.1	111	66%	49.56%	49.7%
18		Stylophora pistillata	Hood coral	Scleractinia	824	XP_022791075.1	111	66%	51.33%	49.7%
19		Salpingoeca rosetta	S. rosetta	Choanoflagellate	1023	XP_004992110.1	102	60%	42.69%	47.9%
20	Fungi	Chytriomyces confervae	Chytrids	Chytridiales	1105	TPX77255	61	36%	39.34%	24.7%
21		Batrachochytrium salamandrivorans	Bsal	Rhizophydiales	1105	OON08604	113	61%	31.03%	33.3%

(*Only partial sequence is shown on NCBI, BLAT is used to make up for the full sequence.)

Time-calibrated phylogenetic tree of CFAP97D2

CFAP97D2 is inferred to first appear in a fungus, Chytridiales (Chytriomyces confervae), at around 1105 MYA. It was highly likely to split from the LOC106699411 gene in the little brown bat (Myotis lucifugus) at around 100 MYA.

The most distantly related species detected so far with CFAP97DF2 ortholog is a fungus called Bsal (Batrachochytrium salamandrivorans) with no isoform. The evolutionary rate of CFAP97D2 is determined to be lower compared to the Fibrinogen alpha gene and slightly faster compared to the Cytochrome c gene. This suggests that the CFAP97D2 gene may have a relatively low mutation rate in fungi and other species.

Interacting Proteins

There was only one known interacting protein: E3 ubiquitin-protein ligase TRIP12 isoform X1. The gene fusion that occurs between trip12 and CFAP97D2 joined them together, allowing these two genes to be transcribed and translated as a single unit. The activity of E3 ubiquitin-protein ligase is strictly regulated by post-translational modifications including phosphorylation and SUMOylation, which may also affect these modification sites on CFAP97D2 protein.

Pathological Significance

It was indicated the expression of CFAP97D2 is affected by Parkinson’s disease. It shows that both protein levels and RNA levels of CFAP97D2 and other tubulin genes undergo a decline, supporting that CFAP97D2 may be highly related to tubulin in human tissue compositions.

Another protein in the CFAP97 gene family, CFAP97D1, functions in both structural components of mammalian sperm flagella and sufficient motility of sperm and affects subsequent fertilization. As CFAP97D1 and CFAP97D2 may have certain interactions with each other, CFAP97D2 is initially expected to be related to sperm motility in mammals.

One literaturely significant variation is found in the 5’-untranslational region, which is a variation in CDC16 gene, cell division cycle 16 homolog in S. cerevisiae. It is a component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The variation in CDC16 was found that have a negative effect dependent on DNA methylation on gene’s expression level.

Single nucleotide polymorphism (SNPs) found in the coding region mostly led to missense. So far, no significant effect was found to connect with human phenotype or conditions.