Fibronectin type III domain–containing protein 9 (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.
Gene FNDC9 is located on the negative strand of human chromosome 5. It is organized into 2 exons forming a single major protein-coding transcript. Expression Bases on human tissue GEO 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.
mRNA The mRNA has 2083 base pairs. There are no isoforms of FNDC9.
Conceptual translation The depicted conceptual translation contains the 5'UTR , protein sequence, and the end of the 3'UTR region.
Protein 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.
Structure The primary structure of human FNDC9 protein contains a signal peptide at the N-terminus, followed by a conserved fibronectin type III (FN3) domain. 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 adopts a β-sandwich fold, and the central portion forms a single α-helical membrane-spanning segment.The C-terminal region is intrinsically disordered.
Protein localization and abundance DeepLoc and PSORT II predict strong enrichment at the cell membrane, with one transmembrane helix supporting membrane insertion. AlphaFold and secondary structure modeling show an extracellular N-terminal domain and a cytoplasmic C-terminal tail, consistent with type I membrane topology.
Post translational modification FNDC9 has multiple significant domains and regions throughout the protein sequence, including a disordered region, a FN3 region/motif, and a transmembrane region. ExPASypredicted post-translational modifications include phosphorylation sites in the C-terminal region and one extracellular N-glycosylation motif: Phosphorylation: NetPhos predictes some phosphorylation sites are predominantly located in the intracellular C-terminal region. Glycosylation: FNDC9 contains one predicted N-glycosylation motif (N-X-S/T) within the extracellular domain.
Evolutionary history
Orthologs 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. It is found in vertebrates, but it is not found in invertebrates. The following table presents some of the orthologs found using BLAST. and EMBOSS NEEDLE Ortholog identity generally decreases with increasing evolutionary distance. FNDC9GenusCommon nameTaxonomicDate of divergence (MYA)Accession numberSequence length(aa)Sequence identity%Similarity%MammalHomo sapiensHumanPrimates0NP_001001343.2224100100Nomascus leucogenysNorthern White-Cheeked GibbonPrimates19.5XP_03068179222498.299.6Sus scrofaPigArtiodactyla94XP_020932357.126085.389.2Mus musculusMouseRodentia87NP_796049.122684.188.5Miniopterus natalensisNatal Long-Fingered BatChiroptera94XP_006863986.122286.692Physeter macrocephalusSperm WhaleCetacea94XP_007115492.22788688.2Antechinus flavipesYellow-Footed AntechinusDasyuromorphia160XP_051834756.121960.974.2AvesGallus gallusChickenGalliformes319XP_015149385.322040.358Egretta garzettaLittle EgretPelecaniformes319XP_009632999.226644.761.5Tyto albaCommon Barn OwlStrigiformes319XP_042644886.121844.643.1AmphibiansAnomaloglossus baeobatrachusGuiana Rocket FrogAnura352XP_075190430 22442.148.1Rhinatrema bivittatumTwo-lined CaecilianGymnophiona352XP_02943948221839.551.5Ambystoma mexicanumAxolotlUrodela352XP_06948780522531.549.5Xenopus tropicalisWestern Clawed FrogAnura352NP_004911868.122625.942.9FishesSalarias fasciatusJewelled BlennyBlenniiformes429XP_029938680.121131.845.3Erpetoichthys calabaricusReed FishPerciformes429XP_051790191.121531.348.1Callorhinchus miliiElephant SharkPolypteriformes462XP_00789103022634.747.9Etheostoma spectabileOrangethroat Darter Polypteriformes429XP_032382694.120831.144.4Polypterus senegalusGray BichirChimaeriformes429XP_039608718.122531.843.9Chiloscyllium plagiosumWhitespotted Bamboo SharkOrectolobiformes462XP_04355612122430.241.7
Rate of divergence 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.
Function
Protein interaction Many proteins have been found to interact with FNDC9. STRING predicts five potential functional partners for FNDC9. Description are depicted in the table below. Abbrev.Full NameBasis of InteractionScoreBiological FunctionPROKR2Prokineticin receptor 2STRING: co-expression, curated literature co-mention; low experimental score0.591GPCR involved in neuroendocrine signaling; activates PLC, Ca²⁺ release, and MAPK pathways.SMIM28Small integral membrane protein 28STRING: Co-Mentioned in Pubmed Abstracts0.582Poorly characterized single-pass membrane protein; possible role in cell communication.VWA3AVon Willebrand factor A domain–containing protein 3ASTRING: predicted functional partner (text mining + homology)0.444ECM-associated adhesion-related protein, domain often used in protein–protein recognition.ANKFN1Ankyrin repeat and fibronectin type III domain–containing protein 1STRING: Co-Mentioned in Pubmed Abstracts0.429Scaffolding protein containing ankyrin repeats; may mediate protein complexes at membranes.FANK1Fibronectin type 3 and ankyrin repeat domains protein 1STRING: Co-Mentioned in Pubmed Abstracts0.406Reported in apoptosis regulation and transcription factor activation.
Clinical significance Some studies occasionally highlight FNDC9 as part of loci associated with neurological and metabolic traits, though without functional validation. In a study of neuroblastoma, FNDC9 was among the genes downregulated in aggressive tumors, associated with extracellular matrix (ECM) organization and neural functions. 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.
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.
References