FNDC9

Fibronectin type III domain–containing protein 9^[5] (FNDC9) is a protein which in humans is encoded by the FNDC9 gene. FNDC9 is a single-pass membrane-associated protein. The protein is expressed across multiple human tissues and appears to play roles in cell signaling and membrane-associated processes.

FNDC9 is located on the negative strand of human chromosome 5. It is organized into 2 exons forming a single major protein-coding transcript.

Bases on human tissue GEO^[6] profile and RNA-seq datasets, FNDC9 shows the highest expression in brain regions, including cortex, cerebellum, and hypothalamus, suggesting potential roles in neural development or signaling.

Reduced expression of FNDC9 in aggressive tumor contexts raises the possibility that FNDC9 contributes to maintaining structural or signaling homeostasis in healthy tissues.

The mRNA has 2083 base pairs. There are no isoforms of FNDC9.

The depicted conceptual translation contains the 5'UTR , protein sequence, and the end of the 3'UTR region.

FNDC9 protein contains 224 amino acid and with molecular mass ~25kDa. It has a theoretical pI of ~5.31, indicating that at physiological pH it will be overall acidic, carrying a net negative charge.^[7]

The primary structure of human FNDC9 protein contains a signal peptide at the N-terminus, followed by a conserved fibronectin type III (FN3) domain.^[9] Approximately between residues 110–130, FNDC9 includes a single-pass transmembrane helix.

Secondary structure predictions indicate that FNDC9 contains ~64% α-helix and ~56% β-strand, along with roughly 10% turns.

At the tertiary level, the N-terminal FN3 domain^[9] adopts a β-sandwich fold, and the central portion forms a single α-helical membrane-spanning segment.The C-terminal region is intrinsically disordered.

DeepLoc^[10] and PSORT II^[11] predict strong enrichment at the cell membrane, with one transmembrane helix supporting membrane insertion. AlphaFold^[8] and secondary structure modeling show an extracellular N-terminal domain and a cytoplasmic C-terminal tail, consistent with type I membrane topology.

FNDC9 has multiple significant domains and regions throughout the protein sequence, including a disordered region, a FN3 region/motif, and a transmembrane region. ExPASy^[12]predicted post-translational modifications include phosphorylation sites in the C-terminal region and one extracellular N-glycosylation motif:

• Phosphorylation: NetPhos^[13] predictes some phosphorylation sites are predominantly located in the intracellular C-terminal region.
• Glycosylation: FNDC9 contains one predicted N-glycosylation motif^[14] (N-X-S/T) within the extracellular domain.

There are many orthologs of Fibronectin type III domain–containing protein 9, both strict and distant, but there are no paralogs. FNDC9 is estimate to have first appeared in fish more than462 years ago.^[15] It is found in vertebrates, but it is not found in invertebrates. The following table presents some of the orthologs found using BLAST.^[16] and EMBOSS NEEDLE^[17] Ortholog identity generally decreases with increasing evolutionary distance.

The increasing corrected sequence divergence with greater evolutionary distance reflects how FNDC9 has gradually diverged since the common ancestor of vertebrates around 430–460 million years ago. Like in Figure 5, FNDC9 evolves faster than highly conserved proteins such as Cytochrome C but slower than rapidly changing proteins like Fibrinogen alpha.

Many proteins have been found to interact with FNDC9. STRING^[18] predicts five potential functional partners for FNDC9. Description are depicted in the table below.

Some studies occasionally highlight FNDC9 as part of loci associated with neurological and metabolic traits, though without functional validation.^[19] In a study of neuroblastoma, FNDC9 was among the genes downregulated in aggressive tumors, associated with extracellular matrix (ECM) organization and neural functions.^[20] Because ECM remodeling is often critical to tumor invasion and metastasis, FNDC9’s altered expression may contribute to tumor behavior in the nervous system or related tissues. In computational analyses, FNDC9 has been noted to exhibit altered regulation during skeletal muscle differentiation, particularly in experiments manipulating PPARγ expression in myoblasts. This suggests a possible role in tissue development or maintenance.^[21]

Although FNDC9 contains several annotated SNPs in genomic databases, no specific human diseases have been definitively linked to this gene. The association of FNDC9 with proteins involved in neuroendocrine signaling (PROKR2), apoptosis (FANK1), and cellular adhesion (VWA3A) suggests possible roles in these biological pathways.^[18]