GNAS complex locus is a gene locus in humans. Its main product is the
heterotrimeric G-protein
Heterotrimeric G protein, also sometimes referred to as the ''"large" G proteins'' (as opposed to the subclass of smaller, monomeric small GTPases) are membrane-associated G proteins that form a heterotrimeric complex. The biggest non-structura ...
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
-regulated
adenylyl cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellular ...
locus
Locus (plural loci) is Latin for "place". It may refer to:
Entertainment
* Locus (comics), a Marvel Comics mutant villainess, a member of the Mutant Liberation Front
* ''Locus'' (magazine), science fiction and fantasy magazine
** ''Locus Award ...
has a highly complex imprinted expression pattern. It gives rise to maternally-, paternally- and biallelically-expressed transcripts that are derived from four alternative promoters with distinct 5'
exons
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequenc ...
. Some transcripts contain a
differentially methylated region
Differentially methylated regions (DMRs) are genomic regions with different DNA methylation status across different biological samples and regarded as possible functional regions involved in gene transcriptional regulation. The biological samples ...
(DMR) within their 5' exons; such DMRs are commonly found in imprinted genes and correlate with transcript expression. An
antisense
In molecular biology and genetics, the sense of a nucleic acid molecule, particularly of a strand of DNA or RNA, refers to the nature of the roles of the strand and its complement in specifying a sequence of amino acids. Depending on the context, ...
transcript also exists, and this antisense transcript and one of the sense transcripts are paternally expressed, produce non-coding RNAs and may regulate imprinting in this region. In addition, one of the transcripts contains a second frame-shifted
open reading frame
In molecular biology, open reading frames (ORFs) are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a Prokaryote, prokaryotic DNA sequence, where only one of the #Six-fra ...
, which encodes a structurally unrelated protein named ALEX.
Products and functions
The GNAS locus is imprinted and encodes 5 main transcripts:
* Gs-α (Gs-α long, P63092-1), biallelic
* A/B transcript (Gs-α short, P63092-2), biallelic: contains an alternate 5' terminal exon (A/B or Exon 1A) and uses a downstream start codon to have a shortened amino terminal region.
**
STX16
Syntaxin-16 is a protein that in humans is encoded by the ''STX16'' gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ...
deletion causes loss of methylation at the A/B exon, leading to PHP1B.
* XLαs (Extra long alpha-s, Q5JWF2), paternal
** ALEX (Alternative gene product encoded by XL-exon, P84996), may inhibit XLαs
* NESP55 (Neuroendocrine secretory protein 55, O95467), maternal
* antisense GNAS transcript (Nespas: neuroendocrine secretory protein antisense)
** Binds to the
PRC2
PRC2 (polycomb repressive complex 2) is one of the two classes of polycomb-group proteins or (PcG). The other component of this group of proteins is PRC1 ( Polycomb Repressive Complex 1).
This complex has histone methyltransferase activity and ...
complex. Abolition of expression causes abnormal methylation and imprinting loss.
Alternative splicing of downstream exons is also observed, which results in different forms of the Gs-α, a key element of the classical signal transduction pathway linking receptor-ligand interactions with the activation of
adenylyl cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
and a variety of cellular responses. Multiple transcript variants have been found for this gene, but the full-length nature and/or biological validity of some variants have not been determined.
Three of the GNAS gene products, Gsα-long, Gsα-short, and XLαs, are different forms of Gsα, and differ mainly in the N-terminal region. Traditional
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
signaling
In signal processing, a signal is a function that conveys information about a phenomenon. Any quantity that can vary over space or time can be used as a signal to share messages between observers. The '' IEEE Transactions on Signal Processing' ...
proceeds primarily through Gsα-long and Gsα-short, the most abundant, ubiquitously-expressed protein products of this gene. XLαs is the "extra large" isoform, and has a very long N-terminal region with some internal repeats not well-conserved across species. The XL exon also encodes in another reading frame the protein product ALEX, an inhibitory cofactor binding to the unique domain. The structure for GNAS is solved for the canonical P63092-1 isoform only, and little is known about what the special region of XLas or ALEX looks like.
NESP55 is a protein product completely unrelated to the GNAS protein. It undergoes extensive posttranslation processing, and is sometimes grouped as a granin. Nearly nothing is known about its structure;
protein structure prediction
Protein structure prediction is the inference of the three-dimensional structure of a protein from its amino acid sequence—that is, the prediction of its secondary and tertiary structure from primary structure. Structure prediction is differen ...
predicts a mostly disordered protein with an N-terminal globular domain made up of alpha-helices.
pseudohypoparathyroidism
Pseudohypoparathyroidism is a condition associated primarily with resistance to the parathyroid hormone. Those with the condition have a low serum calcium and high phosphate, but the parathyroid hormone level (PTH) is appropriately high (due to th ...
McCune–Albright syndrome
McCune–Albright syndrome is a complex genetic disorder affecting the bone, skin and endocrine systems. It is a mosaic disease arising from somatic activating mutations in '' GNAS'', which encodes the alpha-subunit of the Gs heterotrimeric G ...
*
Myxoma
A myxoma (New Latin from Greek 'muxa' for mucus) is a myxoid tumor of primitive connective tissue. It is most commonly found in the heart (and is the most common primary tumor of the heart in adults) but can also occur in other locations.
Ty ...
polyostotic fibrous dysplasia
Polyostotic fibrous dysplasia is a form of fibrous dysplasia affecting more than one bone. Fibrous dysplasia is a disorder where bone is replaced by fibrous tissue, leading to weak bones, uneven growth, and deformity.
McCune-Albright syndrome inc ...
of bone, and some
pituitary tumors
Pituitary adenomas are tumors that occur in the pituitary gland. Most pituitary tumors are benign, approximately 35% are invasive and just 0.1% to 0.2% are carcinomas.increased heart weight, increased
startle reflex
In animals, including humans, the startle response is a largely unconscious defensive response to sudden or threatening stimuli, such as sudden noise or sharp movement, and is associated with negative affect.Rammirez-Moreno, David. "A computation ...
, and abnormalities in bone structure and mineralization; some other alternations can be lethal. Metabolic problems resembling pseudohypoparathyroidism are seen in heterozygous mutated (wt/Oedsml) mice. Knocking out the antisense transcript is known to, at minimum, cause methylation defects.
Interactions
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
-activated Gsα binds to the enzyme
adenylyl cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
, increasing its rate of conversion of
ATP
ATP may refer to:
Companies and organizations
* Association of Tennis Professionals, men's professional tennis governing body
* American Technical Publishers, employee-owned publishing company
* ', a Danish pension
* Armenia Tree Project, non ...
to
cyclic AMP
Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transd ...
.
Gsα has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizat ...
with
RIC8A
Resistance to inhibitors of cholinesterase-8A (Ric-8A), also known as Synembryn-A, is a protein that in humans is encoded by the ''RIC8A'' gene.
Interactions
RIC8A has been shown to interact with GNAO1, GNA13, GNAQ, GNAS complex locus, GNAI2, ...
.
References
Further reading
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External links
*
* WikiGene index for literature mentioning this gene:
** GNAS human ** Nespas
{{Intracellular signaling peptides and proteins
Human proteins