ASpdb: an integrative knowledgebase of human protein isoforms from experimental and AI-predicted structures

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	Protein Summary
	AS Summary
	Protein Functional Features
	Gene Isoform Structures and Expression Levels
	Protein Structures
	pLDDT Score Distribution
	Ramachandran Plot of Protein Structures
	Potential Active Site Information
	Protein Structure and Feature Comparision
	Protein-Protein Interaction
	Related Drugs
	Related Diseases
	Clinically Important Variants

Protein:GNAS

Protein Summary

Gene summary

Gene name: GNAS
ASpdb.0 ID: 2778
	Gene
Gene symbol	GNAS
Gene ID	2778
Gene name	GNAS complex locus
Synonyms	AHO\|C20orf45\|GNAS1\|GPSA\|GSA\|GSP\|NESP\|PITA3\|POH\|SCG6\|SgVI
Cytomap	20q13.32
Type of gene	protein-coding
Description	protein ALEXprotein GNASprotein SCG6 (secretogranin VI)G protein subunit alpha Sadenylate cyclase-stimulating G alpha proteinalternative gene product encoded by XL-exonextra large alphas proteinguanine nucleotide binding protein (G protein), alpha
Modification date	20240416
UniProtAcc	P63092

Gene ontology of this gene with evidence of Inferred from Direct Assay (IDA) from Entrez

Partner	Gene	GO ID	GO term	PubMed ID
Gene	GNAS	GO:0005829	cytosol	12719376
Gene	GNAS	GO:0016020	membrane	12719376

AS Summary

Information of the canonical protein with experimentally identified structure from PDB (2023).

UniProt Acc	File name	PDB ID	Method	Resolution	Chain	Start	End
P63092-1	P63092-1_7cz5_A.pdb	7CZ5	EM	2.6	A	9	394

ASpdb's canonical and alternatively spliced isoform information.

accession_id

gene_name

canonical_id

alternative_id

canonical_length

alternative_length

canonical_start

canonical_end

type

originalSEQ

variationSEQ

alternative_start

alternative_end

P63092

GNAS

P63092-1

P63092-2

394

380

Substitution

P63092

GNAS

P63092-1

P63092-2

394

380

Deletion

none

P63092

GNAS

P63092-1

P63092-3

394

379

Substitution

P63092

GNAS

P63092-1

P63092-3

394

379

Deletion

none

P63092

GNAS

P63092-1

P63092-4

394

395

Substitution

Multiple sequence alignment of our canonical and alternatively spliced GNAS

Matched gene isoform IDs with Ensembl and RefSeq of our canonical and alternative spliced genes of GNAS

UniProt-id	ENSG	ENST	ENSP
P63092-1	ENSG00000087460.29	ENST00000371085.8	ENSP00000360126.3
P63092-2	ENSG00000087460.29	ENST00000371095.7	ENSP00000360136.3
P63092-3	ENSG00000087460.29	ENST00000265620.11	ENSP00000265620.7
P63092-4	ENSG00000087460.29	ENST00000354359.12	ENSP00000346328.7

UniProt-id	NM ID	NP ID
P63092-1	NM_000516.5	NP_000507.1
P63092-2	NM_080426.3	NP_536351.1
P63092-3	NM_001077489.3	NP_001070957.1
P63092-4	NM_001077488.3	NP_001070956.1

Amino acid sequences of our canonical and alternatively spliced GNAS

accession_id	Protein sequence
P63092-1	MGCLGNSKTEDQRNEEKAQREANKKIEKQLQKDKQVYRATHRLLLLGAGESGKSTIVKQMRILHVNGFNGEGGEEDPQAARSNSDGEKAT KVQDIKNNLKEAIETIVAAMSNLVPPVELANPENQFRVDYILSVMNVPDFDFPPEFYEHAKALWEDEGVRACYERSNEYQLIDCAQYFLD KIDVIKQADYVPSDQDLLRCRVLTSGIFETKFQVDKVNFHMFDVGGQRDERRKWIQCFNDVTAIIFVVASSSYNMVIREDNQTNRLQEAL NLFKSIWNNRWLRTISVILFLNKQDLLAEKVLAGKSKIEDYFPEFARYTTPEDATPEPGEDPRVTRAKYFIRDEFLRISTASGDGRHYCY
P63092-2	MGCLGNSKTEDQRNEEKAQREANKKIEKQLQKDKQVYRATHRLLLLGAGESGKSTIVKQMRILHVNGFNGDSEKATKVQDIKNNLKEAIE TIVAAMSNLVPPVELANPENQFRVDYILSVMNVPDFDFPPEFYEHAKALWEDEGVRACYERSNEYQLIDCAQYFLDKIDVIKQADYVPSD QDLLRCRVLTSGIFETKFQVDKVNFHMFDVGGQRDERRKWIQCFNDVTAIIFVVASSSYNMVIREDNQTNRLQEALNLFKSIWNNRWLRT ISVILFLNKQDLLAEKVLAGKSKIEDYFPEFARYTTPEDATPEPGEDPRVTRAKYFIRDEFLRISTASGDGRHYCYPHFTCAVDTENIRR
P63092-3	MGCLGNSKTEDQRNEEKAQREANKKIEKQLQKDKQVYRATHRLLLLGAGESGKSTIVKQMRILHVNGFNGDEKATKVQDIKNNLKEAIET IVAAMSNLVPPVELANPENQFRVDYILSVMNVPDFDFPPEFYEHAKALWEDEGVRACYERSNEYQLIDCAQYFLDKIDVIKQADYVPSDQ DLLRCRVLTSGIFETKFQVDKVNFHMFDVGGQRDERRKWIQCFNDVTAIIFVVASSSYNMVIREDNQTNRLQEALNLFKSIWNNRWLRTI SVILFLNKQDLLAEKVLAGKSKIEDYFPEFARYTTPEDATPEPGEDPRVTRAKYFIRDEFLRISTASGDGRHYCYPHFTCAVDTENIRRV
P63092-4	MGCLGNSKTEDQRNEEKAQREANKKIEKQLQKDKQVYRATHRLLLLGAGESGKSTIVKQMRILHVNGFNGEGGEEDPQAARSNSDGSEKA TKVQDIKNNLKEAIETIVAAMSNLVPPVELANPENQFRVDYILSVMNVPDFDFPPEFYEHAKALWEDEGVRACYERSNEYQLIDCAQYFL DKIDVIKQADYVPSDQDLLRCRVLTSGIFETKFQVDKVNFHMFDVGGQRDERRKWIQCFNDVTAIIFVVASSSYNMVIREDNQTNRLQEA LNLFKSIWNNRWLRTISVILFLNKQDLLAEKVLAGKSKIEDYFPEFARYTTPEDATPEPGEDPRVTRAKYFIRDEFLRISTASGDGRHYC

Protein Functional Features

Main function of this protein. (from UniProt)

GNAS (go to UniProt):P63092

Retention analysis result of protein across 39 protein features of UniProt such as six molecule processing features, 13 region features, four site features, six amino acid modification features, two natural variation features, five experimental info features, and 3 secondary structure features. Here, because of limited space for viewing, we only show the protein feature retention information belong to the 13 regional features. All retention annotation result can be downloaded at
download page
* Minus value of BPloci means that the break pointn is located before the CDS.

- Retained protein feature among the 13 regional features.

Accession_id	Subsection	Start	End	Funcitonal feature	Splicing information
P63092	Domain	39	394	Note=G-alpha;Ontology_term=ECO:0000255;evidence=ECO:0000255\|PROSITE-ProRule:PRU01230	Type=Substitution;Start=71;End=72
P63092	Domain	39	394	Note=G-alpha;Ontology_term=ECO:0000255;evidence=ECO:0000255\|PROSITE-ProRule:PRU01230	Type=Deletion;Start=73;End=86
P63092	Domain	39	394	Note=G-alpha;Ontology_term=ECO:0000255;evidence=ECO:0000255\|PROSITE-ProRule:PRU01230	Type=Substitution;Start=71;End=71
P63092	Domain	39	394	Note=G-alpha;Ontology_term=ECO:0000255;evidence=ECO:0000255\|PROSITE-ProRule:PRU01230	Type=Deletion;Start=72;End=86
P63092	Domain	39	394	Note=G-alpha;Ontology_term=ECO:0000255;evidence=ECO:0000255\|PROSITE-ProRule:PRU01230	Type=Substitution;Start=86;End=86
P63092	Region	68	91	Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256\|SAM:MobiDB-lite	Type=Substitution;Start=71;End=72
P63092	Region	68	91	Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256\|SAM:MobiDB-lite	Type=Deletion;Start=73;End=86
P63092	Region	68	91	Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256\|SAM:MobiDB-lite	Type=Substitution;Start=71;End=71
P63092	Region	68	91	Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256\|SAM:MobiDB-lite	Type=Deletion;Start=72;End=86
P63092	Region	68	91	Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256\|SAM:MobiDB-lite	Type=Substitution;Start=86;End=86

Gene Isoform Structures and Expression Levels for GNAS

Gene structures of our canonical and alternative spliced genes of GNAS
* Click on the image to open the UCSC genome browser with custom track showing this image in a new window.

Expression levels of gene isoforms across GTEx.

Expression levels of gene isoforms across TCGA.

Protein Structures

PDB and CIF files of the predicted protein structures
* Here we show the 3D structure of the proteins using Mol*. AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100. Model confidence is shown from the pLDDT values per residue. pLDDT corresponds to the model’s prediction of its score on the local Distance Difference Test. It is a measure of local accuracy (from AlphfaFold website). To color code individual residues, we transformed individual PDB files into CIF format.

3D view using mol* of P63092-1

3D view using mol* of P63092-2

3D view using mol* of P63092-3

3D view using mol* of P63092-4

pLDDT Score Distribution

pLDDT score distribution of the predicted protein structures from AlphaFold2
* AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100.

pLDDT distribution across the protein length of P63092-1

pLDDT distribution across the protein length of P63092-2

pLDDT distribution across the protein length of P63092-3

pLDDT distribution across the protein length of P63092-4

Ramachandran Plot of Protein Structures

Ramachandran plot of the torsional angles - phi (φ)and psi (ψ) - of the residues (amino acids) contained in this protein peptide.

Ramachandran plot of P63092-1

Ramachandran plot of P63092-2

Ramachandran plot of P63092-3

Potential Active Site Information

The potential binding sites of these proteins were identified using SiteMap, a module of the Schrodinger suite.

UniProt-id	Site score	Size	D score	Volume	Exposure	Enclosure	Contact	Phobic	Philic	Balance	Don/Acc	Residues
P63092-1	1.137	248	1.036	409.199	0.251	0.903	1.147	0.818	1.367	0.598	0.563	49,50,51,52,53,54,55,57,58,61,68,87,91,94,172,173, 174,198,199,200,201,202,203,204,205,208,223,224,22 5,226,227,258,292,293,295,296,365,366,367
P63092-2	1.119	219	1.022	391.363	0.316	0.875	1.146	0.744	1.358	0.548	0.582	49,50,51,52,53,54,55,57,58,61,68,77,158,159,160,18 4,185,186,187,188,189,190,194,209,210,211,212,213, 278,279,281,282,352,353
P63092-3	1.119	247	1.08	444.185	0.31	0.876	1.155	1.041	1.183	0.88	0.607	49,50,51,52,53,54,55,57,58,61,68,72,76,157,158,159 ,162,182,183,184,185,186,187,188,189,190,193,195,2 08,209,210,211,212,243,277,278,280,281,350,351,352
P63092-4	1.057	336	1.058	850.297	0.481	0.784	0.997	0.747	1.08	0.692	0.624	33,36,37,40,49,50,51,52,53,54,55,57,58,61,64,65,66 ,67,68,69,72,73,75,76,79,83,88,91,92,95,173,174,17 5,198,199,200,201,202,203,204,205,209,211,212,213, 214,219,220,221,224,225,226,227,228,259,293,294,29 6,297,366,367,368

Protein Structure and Feature Comparision

Protein Structure Comparision Using Template Modeling Scores (TM-score).

Protein Structure Comparision Visualization with mol*. between Canonical predicted structure (AF2)(orange) vs Canonical validated structure (PDB)(green)

3D view using mol* of P63092-1_P63092-1_7cz5_A.pdb

Protein Structure Comparision Visualization with mol*. between Canonical validated structure (PDB)(orange) vs Alternative predicted structure (AF2)(green)

3D view using mol* of P63092-1_7cz5_A_P63092-2.pdb

3D view using mol* of P63092-1_7cz5_A_P63092-3.pdb

3D view using mol* of P63092-1_7cz5_A_P63092-4.pdb

Protein Structure Comparision Visualization with mol*. between Canonical predicted structure (AF2)(orange) vs Alternative predicted structure (AF2)(green)

3D view using mol* of P63092-1_P63092-2.pdb

3D view using mol* of P63092-1_P63092-3.pdb

3D view using mol* of P63092-1_P63092-4.pdb

Protein Feature Comparison of the protein sequendary structures among the protiens.

./stats/secondary_structure/figure/P63092-1_vs_P63092-2.png

./stats/secondary_structure/figure/P63092-1_vs_P63092-3.png

./stats/secondary_structure/figure/P63092-1_vs_P63092-4.png

Protein Feature Comparison of the relative accessible surface area (ASA) among the protiens.

./stats/relative_asa/P63092-1_vs_P63092-2.png

./stats/relative_asa/P63092-1_vs_P63092-3.png

./stats/relative_asa/P63092-1_vs_P63092-4.png

Protein-Protein Interaction

Interactors from UniProt.

Accession_id

Subsection

Start

End

Funcitonal feature

Splicing information

Interactors from STRING.

Gene name

Interactors

Related Drugs to GNAS

Drugs targeting this gene/protein.
(DrugBank)

UniProt accession	Gene name	DrugBank ID	Drug name	Drug group	Actions
P63092	GNAS	DB02587	Colforsin	experimental, investigational
P63092	GNAS	DB06843	2',5'-DIDEOXY-ADENOSINE 3'-MONOPHOSPHATE	experimental

Related Diseases to GNAS

Previous studies relating to the alternative splicing of GNAS and disease information from the MeSH term (PubMed)

Gene	PMID	Title	Abstract	MeSH ID	MeSH term
GNAS	9860993	Bidirectional imprinting of a single gene: GNAS1 encodes maternally, paternally, and biallelically derived proteins.	The GNAS1 gene encodes the alpha subunit of the guanine nucleotide-binding protein Gs, which couples signaling through peptide hormone receptors to cAMP generation. GNAS1 mutations underlie the hormone resistance syndrome pseudohypoparathyroidism type Ia (PHP-Ia), so the maternal inheritance displayed by PHP-Ia has raised suspicions that GNAS1 is imprinted. Despite this suggestion, in most tissues Gsalpha is biallelically encoded. In contrast, the large G protein XLalphas, also encoded by GNAS1, is paternally derived. Because the inheritance of PHP-Ia predicts the existence of maternally, rather than paternally, expressed transcripts, we have investigated the allelic origin of other mRNAs derived from GNAS1. We find this gene to be remarkable in the complexity of its allele-specific regulation. Two upstream promoters, each associated with a large coding exon, lie only 11 kb apart, yet show opposite patterns of allele-specific methylation and monoallelic transcription. The more 5' of these exons encodes the neuroendocrine secretory protein NESP55, which is expressed exclusively from the maternal allele. The NESP55 exon is 11 kb 5' to the paternally expressed XLalphas exon. The transcripts from these two promoters both splice onto GNAS1 exon 2, yet share no coding sequences. Despite their structural unrelatedness, the encoded proteins, of opposite allelic origin, both have been implicated in regulated secretion in neuroendocrine tissues. Remarkably, maternally (NESP55), paternally (XLalphas), and biallelically (Gsalpha) derived proteins all are produced by different patterns of promoter use and alternative splicing of GNAS1, a gene showing simultaneous imprinting in both the paternal and maternal directions.	D011547	Pseudohypoparathyroidism
GNAS	24711643	Identifying biological pathways that underlie primordial short stature using network analysis.	Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure.	D004392	Dwarfism
GNAS	24711643	Identifying biological pathways that underlie primordial short stature using network analysis.	Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure.	D006130	Growth Disorders
GNAS	24711643	Identifying biological pathways that underlie primordial short stature using network analysis.	Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure.	D009123	Muscle Hypotonia

Clinically important variants in GNAS

(ClinVar, 04/20/2024)

accession_id

uniprot_id

gene_name

Type

Variant

Clinical_significance