| ARL6IP6 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | ARL6IP6 , AIP-6, PFAAP1, AIP6, ADP ribosylation factor like GTPase 6 interacting protein 6 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 616495; MGI: 1929507; HomoloGene: 11302; GeneCards: ARL6IP6; OMA:ARL6IP6 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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ADP ribosylation factor like GTPase 6 interacting protein 6 is a protein that in the humans is encoded by the ARL6IP6 gene. [4] [5] [6] It spans from 152,717,893 to 152,761,253 on the plus strand.
ARL6IP6 Also known as Phosphonoformate Immuno-Associated Protein 1. It has 43,361 bases and 11 exons and is located on the long arm of chromosome 2, at 2q23.3 in humans. [7] In humans there are three upstream genes (PRPF40A, FMNL2 and STAM2) and three downstream genes (GALNT13, KCNJ3, NR4A2) that define the identity of this genomic region. [8]
ARL6IP6 protein is approximately 226 amino acids in length. The ARL6IP6 gene undergoes alternative splicing, post transcription, that results in multiple transcript variants. These variants encode protein isoforms of different lengths that include isoforms of 226, 195 and 130 amino acids. Isoforms, which are variations in protein structure and function produced by the same gene, indicate that the ARL6IP6 protein may have varying functions depending on the tissue or environment it is synthesized in. As of this moment, the differences between ARL6IP6 isoforms and their respective function remain unknown. No three-dimensional structure of ARL6IP6 has been confirmed.
Proteins that are of a similar size and make-up usually posses regions that contribute to interactions between proteins and membranes, however, these regions have not yet been identified in ARL6IP6's structure. Computational modeling, like the one found AlphaFold, have generated predicted three-dimensional structures of ARL6IP6 that suggest its conformation to be majority a-helical. These models are algorithm based predictions and have not been validated through techniques like X-ray crystallography or nuclear magnetic resonance (NMR) spectroscopy.
The structural variation of ARL6IP6 isoforms produced by alternative splicing may influence protein stability, localization or interaction with other cellular components. In many other genes, isoforms that resulted from alternative splicing can have distinct and sometimes contrasting roles, these however, have not been confirmed in ARL6IP6. The lack of experimentally confirmed structural data reflects the limited characterization available for this protein.
The exact function of ARL6IP6 is unknown. ARL6IP6 is known to interact with ADP-ribosylation factor-like (ARL) proteins, which are members of GTPases family that play roles in intracellular membrane transportation. Proteins that interact with these ARL proteins are typically involved in regulation of these processes. Based on this association, ARL6IP6 may play a role in membrane-related or intracellular transport pathways. Proteomic analyses suggested that ARL6IP6 localized to the inner nuclear membrane of certain mesenchymal cells, including adipocytes and myocytes. The location of ARL6IP indicates possible involvement in nuclear envelopment organization or nucleocytoplasmic signaling processes. [9]
Additionally, an increase in the expression of ARL6IP6 in cumulus cells has been documented in aged mares when compared to younger animals. This suggests that a link to age related declines in oocyte quality is possible. [10] Furthermore, in pigs, post transcriptional regulation of ARL6IP6 has been observed where it has been targeted by microRNA miR-26 during Salmonella infection. This indicates a potential role in the immune or inflammatory response pathways. [11]
Jointly, these findings suggest that ARL6IP6 may function in the junction of membrane trafficking, cell organization and stress-response pathways. it is important to note, however, that the it's full function has not been characterized.
ARL6IP6 mutations have been linked to both neurological and vascular malfunctions. A 2015 study reported a patient with a loss-of-function mutation who presented with cutis marmorata telangiectatic congenita (CMTC), which resulted in vascular abnormalities, developmental delays and transient ischemic attacks (strokes). [12] Literature reviews have reported mutations in additional patients with CMTC and strokes but the functional consequences of these mutations remain unknown. [13] Additionally, a genome-wide study identified a single nucleotide polymorphism (SNP), rs1986743, located in an intron of ARL6IP6 that displayed suggestive association (P = 2.7 × 10⁻⁷) with early onset ischemic stroke, but did not reach genome-wide significance. [14]
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