UniProtKB/Swiss-Prot O95278: Variant p.Trp32Gly

Laforin
Gene: EPM2A
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Variant information Variant position:

32 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant:

LP/P [Disclaimer] The variants are classified into three categories: LP/P, LB/B and US.

LP/P: likely pathogenic or pathogenic.
LB/B: likely benign or benign.
US: uncertain significance

Residue change:

From Tryptophan (W) to Glycine (G) at position 32 (W32G, p.Trp32Gly). Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.
Physico-chemical properties:

Change from large size and aromatic (W) to glycine (G) The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score:

-2 The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:

Lowest score: -4 (low probability of substitution).
Highest score: 11 (high probability of substitution).

More information can be found on the following page
Variant description:

In MELF1; impairs protein stability; affects phosphatase activity; abolishes glycogen binding; abolishes phosphatase activity with insoluble glucan; disrupts the interaction with PPP1R3C. Any additional useful information about the variant.
Other resources:

Links to websites of interest for the variant.

Variant rs104893955 [ dbSNP | Ensembl ]

Sequence information Variant position:

32 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length:

331 The length of the canonical sequence.
Location on the sequence:

AVAGARPELLVVGSRPELGR W EPRGAVRLRPAGTAAGDGAL The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.
Residue conservation:

The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         AVAGARPELLVVGSRPELGRWEPRGAVRLRPAGTAAGDGAL

                              AGAGAAPELLVVGSRPELGRWEPRGAVRLRPAGSAAGGGAR

Mouse                         AVAGARQELLLAGSRPELGRWEPHGAVRLRPAGTAAGAAAL

Rat                           AVAGTRLELLLAGSRPELGRWEPRGAVRLRPAGTAAGAAAL

Sequence annotation in neighborhood:

The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:

Type: the type of sequence feature.
Positions: endpoints of the sequence feature.
Description: contains additional information about the feature.

Type	Positions	Description
Chain	1 – 331	Laforin
Domain	1 – 124	CBM20
Binding site	32 – 32
Modified residue	25 – 25	Phosphoserine; by AMPK
Alternative sequence	1 – 243	Missing. In isoform 6.
Alternative sequence	1 – 159	MRFRFGVVVPPAVAGARPELLVVGSRPELGRWEPRGAVRLRPAGTAAGDGALALQEPGLWLGEVELAAEEAAQDGAEPGRVDTFWYKFLKREPGGELSWEGNGPHHDRCCTYNENNLVDGVYCLPIGHWIEATGHTNEMKHTTDFYFNIAGHQAMHYSR -> MIFNK. In isoform 7.
Alternative sequence	1 – 138	Missing. In isoform 8.
Mutagenesis	25 – 25	S -> A. Partial loss of phosphatase activity. Abolishes homodimerization. Abolishes interaction with NHLRC1, PPP1R3C and PRKAA2. Does not affect glycogen binding. Reduces stability of the protein.
Mutagenesis	25 – 25	S -> D. Partial loss of phosphatase activity. Increases interaction with NHLRC1. Does not affect interaction with NHLRC1, PPP1R3C or PRKAA2. Does not affect binding to carbohydrate. Does not affect homodimerization.
Turn	30 – 32

Literature citations
A unique carbohydrate binding domain targets the Lafora disease phosphatase to glycogen.
Wang J.; Stuckey J.A.; Wishart M.J.; Dixon J.E.;
J. Biol. Chem. 277:2377-2380(2002)
Cited for: GLYCOGEN-BINDING; DOMAIN; SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANT MELF1 GLY-32; CATALYTIC ACTIVITY; ACTIVE SITE; MUTAGENESIS OF LYS-87 AND CYS-266; Laforin, the dual-phosphatase responsible for Lafora disease, interacts with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances glycogen accumulation.
Fernandez-Sanchez M.E.; Criado-Garcia O.; Heath K.E.; Garcia-Fojeda B.; Medrano-Fernandez I.; Gomez-Garre P.; Sanz P.; Serratosa J.M.; Rodriguez de Cordoba S.;
Hum. Mol. Genet. 12:3161-3171(2003)
Cited for: FUNCTION; CATALYTIC ACTIVITY; SELF-INTERACTION; SUBCELLULAR LOCATION; GLYCOGEN-BINDING; INTERACTION WITH PPP1R3C; TISSUE SPECIFICITY; MUTAGENESIS OF ASP-235 AND CYS-266; ACTIVE SITE; CHARACTERIZATION OF VARIANTS MELF1 GLY-32; LEU-84; CYS-108; ILE-194; SER-240; SER-279; LEU-293; ASN-294 AND LEU-301; The carbohydrate-binding domain of Lafora disease protein targets Lafora polyglucosan bodies.
Ganesh S.; Tsurutani N.; Suzuki T.; Hoshii Y.; Ishihara T.; Delgado-Escueta A.V.; Yamakawa K.;
Biochem. Biophys. Res. Commun. 313:1101-1109(2004)
Cited for: BINDING TO GLYCOGEN AND LAFORA BODIES; DOMAIN; CHARACTERIZATION OF VARIANTS MELF1 PRO-25; LYS-28; GLY-32 AND LEU-88; CHARACTERIZATION OF VARIANT PRO-46; Mechanistic insights into glucan phosphatase activity against polyglucan substrates.
Meekins D.A.; Raththagala M.; Auger K.D.; Turner B.D.; Santelia D.; Koetting O.; Gentry M.S.; Vander Kooi C.W.;
J. Biol. Chem. 290:23361-23370(2015)
Cited for: CATALYTIC ACTIVITY; FUNCTION; MOTIF; CHARACTERIZATION OF VARIANT MELF1 GLY-32; Structural mechanism of laforin function in glycogen dephosphorylation and lafora disease.
Raththagala M.; Brewer M.K.; Parker M.W.; Sherwood A.R.; Wong B.K.; Hsu S.; Bridges T.M.; Paasch B.C.; Hellman L.M.; Husodo S.; Meekins D.A.; Taylor A.O.; Turner B.D.; Auger K.D.; Dukhande V.V.; Chakravarthy S.; Sanz P.; Woods V.L. Jr.; Li S.; Vander Kooi C.W.; Gentry M.S.;
Mol. Cell 57:261-272(2015)
Cited for: X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 1-329 IN COMPLEX WITH MALTOHEXAOSE AND PHOSPHATE; CATALYTIC ACTIVITY; FUNCTION; SUBUNIT; MUTAGENESIS OF VAL-8; LYS-87; TRP-99; ILE-126; THR-142; ASP-197; MET-236 AND CYS-266; CHARACTERIZATION OF VARIANTS MELF1 GLY-32; HIS-171; SER-240; ASN-294 AND LEU-301; Genotype-phenotype correlations for EPM2A mutations in Lafora's progressive myoclonus epilepsy: exon 1 mutations associate with an early-onset cognitive deficit subphenotype.
Ganesh S.; Delgado-Escueta A.V.; Suzuki T.; Francheschetti S.; Riggio C.; Avanzini G.; Rabinowicz A.; Bohlega S.; Bailey J.; Alonso M.E.; Rasmussen A.; Thomson A.E.; Ochoa A.; Prado A.J.; Medina M.T.; Yamakawa K.;
Hum. Mol. Genet. 11:1263-1271(2002)
Cited for: VARIANTS MELF1 PRO-25; CYS-108; HIS-171 AND LEU-293; CHARACTERIZATION OF VARIANTS MELF1 GLY-32; CYS-108; ILE-194; SER-279 AND ASN-294;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.