UniProtKB/Swiss-Prot Q13501: Variant p.Met404Thr

Gene: SQSTM1
Chromosomal location: 5q35
Variant information

Variant position:  404
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Methionine (M) to Threonine (T) at position 404 (M404T, p.Met404Thr).
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 medium size and hydrophobic (M) to medium size and polar (T)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -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

Involvement in disease:  Paget disease of bone 3 (PDB3) [MIM:167250]: A disorder of bone remodeling characterized by increased bone turnover affecting one or more sites throughout the skeleton, primarily the axial skeleton. Osteoclastic overactivity followed by compensatory osteoblastic activity leads to a structurally disorganized mosaic of bone (woven bone), which is mechanically weaker, larger, less compact, more vascular, and more susceptible to fracture than normal adult lamellar bone. {ECO:0000269|PubMed:11992264, ECO:0000269|PubMed:12374763, ECO:0000269|PubMed:14584883, ECO:0000269|PubMed:15125799, ECO:0000269|PubMed:15146436, ECO:0000269|PubMed:15176995, ECO:0000269|PubMed:15207768, ECO:0000269|PubMed:19931284}. Note=The disease is caused by mutations affecting the gene represented in this entry.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In PDB3.
Any additional useful information about the variant.

Sequence information

Variant position:  404
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  440
The length of the canonical sequence.

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.




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.

Chain 2 – 440 Sequestosome-1
Domain 389 – 434 UBA
Region 269 – 440 Interaction with NTRK1
Modified residue 403 – 403 Phosphoserine; by ULK1
Mutagenesis 398 – 398 L -> V. No effect on polyubiquitin-binding.
Mutagenesis 406 – 406 F -> V. Loss of polyubiquitin-binding.
Mutagenesis 409 – 409 E -> K. Decreased activation of NF-kappa-B.
Mutagenesis 410 – 410 G -> K. Decreased activation of NF-kappa-B.
Mutagenesis 413 – 413 L -> V. No effect on polyubiquitin-binding.
Mutagenesis 417 – 417 L -> V. Loss of polyubiquitin-binding.
Turn 403 – 405

Literature citations

Familial Paget's disease in The Netherlands: occurrence, identification of new mutations in the sequestosome 1 gene, and their clinical associations.
Eekhoff E.W.M.; Karperien M.; Houtsma D.; Zwinderman A.H.; Dragoiescu C.; Kneppers A.L.J.; Papapoulos S.E.;
Arthritis Rheum. 50:1650-1654(2004)
Cited for: VARIANTS PDB3 LEU-392; PRO-399; THR-404 AND ARG-425;

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.