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UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot Q9UQ13: Variant p.Met173Ile

Leucine-rich repeat protein SHOC-2
Gene: SHOC2
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Variant information Variant position: help 173 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant: help 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: help From Methionine (M) to Isoleucine (I) at position 173 (M173I, p.Met173Ile). 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: help Similar physico-chemical property. Both residues are medium size and hydrophobic. The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score: help 1 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: help In NSLH1; significantly decreases ERK1/2 activity; does not affect cytoplasm and nucleus localization; does not affect SHOC2-MRAS-RAF1 complex assembly; impairs interaction with phosphatase 1c; promotes SMP complex formation; promotes dephosphorylation of 'S-365' of BRAF by SMP complex. Any additional useful information about the variant.
Other resources: help Links to websites of interest for the variant.


Sequence information Variant position: help 173 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length: help 582 The length of the canonical sequence.
Location on the sequence: help LSENSLTSLPDSLDNLKKLR M LDLRHNKLREIPSVVYRLDS 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: help The multiple alignment of the region surrounding the variant against various orthologous sequences.
Human                         LSENSLTSLPDSLDNLKKLRMLDLRHNKLREIPSVVYRLDS

Mouse                         LSENSLTSLPDSLDNLKKLRMLDLRHNKLREIPSVVYRLDS

Rat                           LSENSLTSLPDSLDNLKKLRMLDLRHNKLREIPSVVYRLDS

Bovine                        LSENSLTSLPDSLDNLKKLRMLDLRHNKLREIPSVVYRLDS

Chicken                       LSENSLTSLPDSLDNLKKLRMLDLRHNKLREIPSVVYRLTS

Xenopus laevis                LSENSLTSLPDSLDNLKKLCMLDLRHNKLREIPPVVYRLSS

Zebrafish                     LSENSLTSLPDSLDNLKKLRMLDLRHNKLREIPAVVYRVSS

Caenorhabditis elegans        LSENALTSLPDSLASLESLETLDLRHNKLTEVPSVIYKIGS

Sequence annotation in neighborhood: help 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.
TypePositionsDescription
Chain 1 – 582 Leucine-rich repeat protein SHOC-2
Repeat 170 – 191 LRR 4
Mutagenesis 155 – 155 E -> A. Impairs SMP complex formation.
Mutagenesis 175 – 175 D -> N. Abolishes SMP complex formation.
Mutagenesis 177 – 177 R -> A. Abolishes SMP complex formation.
Mutagenesis 180 – 180 K -> E. Impairs SMP complex formation; when associated with E-134 and E-226.
Beta strand 173 – 175



Literature citations
A Novel SHOC2 Variant in Rasopathy.
Hannig V.; Jeoung M.; Jang E.R.; Phillips J.A. III; Galperin E.;
Hum. Mutat. 35:1290-1294(2014)
Cited for: VARIANT NSLH1 ILE-173; CHARACTERIZATION OF VARIANT NSLH1 ILE-173; FUNCTION; INTERACTION WITH MRAS AND RAF1 AND PHOSPHATASE 1C; SUBCELLULAR LOCATION; Structure of the SHOC2-MRAS-PP1c complex provides insights into RAF activation and Noonan syndrome.
Bonsor D.A.; Alexander P.; Snead K.; Hartig N.; Drew M.; Messing S.; Finci L.I.; Nissley D.V.; McCormick F.; Esposito D.; Rodriguez-Viciana P.; Stephen A.G.; Simanshu D.K.;
Nat. Struct. Mol. Biol. 29:966-977(2022)
Cited for: X-RAY CRYSTALLOGRAPHY (2.17 ANGSTROMS) OF 2-582 IN COMPLEX WITH PPP1CA AND MRAS; FUNCTION; INTERACTION WITH PPP1CA; PPP1CB; MRAS; KRAS; NRAS AND HRAS; DOMAIN; LRR REPEATS; MUTAGENESIS OF VAL-64; PHE-66; TYR-129; TYR-131; GLU-155; ASP-175; ARG-177 AND ARG-223; CHARACTERIZATION OF VARIANT ILE-173; Structural basis for SHOC2 modulation of RAS signalling.
Liau N.P.D.; Johnson M.C.; Izadi S.; Gerosa L.; Hammel M.; Bruning J.M.; Wendorff T.J.; Phung W.; Hymowitz S.G.; Sudhamsu J.;
Nature 609:400-407(2022)
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (2.95 ANGSTROMS) OF 2-582 IN COMPLEX WITH PPP1CC AND MRAS; X-RAY CRYSTALLOGRAPHY (3.19 ANGSTROMS) OF 2-582; FUNCTION; INTERACTION WITH PPP1CA; PPP1CB; PPP1CC; MRAS; KRAS; NRAS AND HRAS; DOMAIN; LRR REPEATS; MUTAGENESIS OF LYS-109; LYS-134; ASP-175; LYS-180; LYS-226; GLN-269; HIS-270; GLU-457 AND GLU-503; CHARACTERIZATION OF VARIANT ILE-173; Structure-function analysis of the SHOC2-MRAS-PP1c holophosphatase complex.
Kwon J.J.; Hajian B.; Bian Y.; Young L.C.; Amor A.J.; Fuller J.R.; Fraley C.V.; Sykes A.M.; So J.; Pan J.; Baker L.; Lee S.J.; Wheeler D.B.; Mayhew D.L.; Persky N.S.; Yang X.; Root D.E.; Barsotti A.M.; Stamford A.W.; Perry C.K.; Burgin A.; McCormick F.; Lemke C.T.; Hahn W.C.; Aguirre A.J.;
Nature 609:408-415(2022)
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (2.89 ANGSTROMS) OF IN COMPLEX WITH PPP1CA AND MRAS; X-RAY CRYSTALLOGRAPHY (1.79 ANGSTROMS) OF 88-581; FUNCTION; INTERACTION WITH PPP1CA; PPP1CB; PPP1CC; MRAS; KRAS; NRAS AND HRAS; DOMAIN; LRR REPEATS; MUTAGENESIS OF VAL-64; PHE-66; TYR-131; ARG-223 AND GLU-457; CHARACTERIZATION OF VARIANT ILE-173; Structure of the MRAS-SHOC2-PP1C phosphatase complex.
Hauseman Z.J.; Fodor M.; Dhembi A.; Viscomi J.; Egli D.; Bleu M.; Katz S.; Park E.; Jang D.M.; Porter K.A.; Meili F.; Guo H.; Kerr G.; Molle S.; Velez-Vega C.; Beyer K.S.; Galli G.G.; Maira S.M.; Stams T.; Clark K.; Eck M.J.; Tordella L.; Thoma C.R.; King D.A.;
Nature 609:416-423(2022)
Cited for: X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 80-582 IN COMPLEX WITH PPP1CA AND MRAS; FUNCTION; INTERACTION WITH PPP1CA; MRAS; KRAS AND NRAS; DOMAIN; LRR REPEATS; CHARACTERIZATION OF VARIANT ILE-173;
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.