UniProtKB/Swiss-Prot Q13501: Variant p.Pro392Leu

Sequestosome-1
Gene: SQSTM1
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Variant information Variant position:

392 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 Proline (P) to Leucine (L) at position 392 (P392L, p.Pro392Leu). 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:

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:

-3 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 PDB3 and FTDALS3; no effect on polyubiquitin-binding. Any additional useful information about the variant.
Other resources:

Links to websites of interest for the variant.

Variant rs104893941 [ dbSNP | Ensembl ]

Sequence information Variant position:

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

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

EGPTGLKEAALYPHLPPEAD P RLIESLSQMLSMGFSDEGGW 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                         EGPTGLKEAALYPHLPPEADPRLIESLSQMLSMGFSDEGGW

Mouse                         EGPTGLKEAALYPHLPPEADPRLIESLSQMLSMGFSDEGGW

Rat                           EGPTGLKEAALYPHLPPEADPRLIESLSQMLSMGFSDEGGW

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	2 – 440	Sequestosome-1
Domain	389 – 434	UBA
Region	269 – 440	Interaction with NTRK1
Modified residue	403 – 403	Phosphoserine; by CK2, ULK1 and TBK1
Modified residue	407 – 407	Phosphoserine; by ULK1
Mutagenesis	398 – 398	L -> V. No effect on polyubiquitin-binding.
Mutagenesis	403 – 403	S -> A. Abolished phosphorylation by CK2, leading to decreased affinity for ubiquitinated proteins. Abolished ability to promote relocalization of 'Lys-63'-linked ubiquitinated STING1 to autophagosomes.
Mutagenesis	403 – 403	S -> E. Mimmics phosphorylation; increased affinity for ubiquitinated proteins, leading to increased p62 body formation and autophagic degradation.
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.
Helix	392 – 402

Literature citations
SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis.
Fecto F.; Yan J.; Vemula S.P.; Liu E.; Yang Y.; Chen W.; Zheng J.G.; Shi Y.; Siddique N.; Arrat H.; Donkervoort S.; Ajroud-Driss S.; Sufit R.L.; Heller S.L.; Deng H.X.; Siddique T.;
Arch. Neurol. 68:1440-1446(2011)
Cited for: INVOLVEMENT IN FTDALS3; VARIANTS FTDALS3 VAL-33; ILE-153; LEU-228; LYS-238 DEL; PRO-318; CYS-321; PRO-370; LEU-392; SER-411 AND ARG-425; SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis.
Le Ber I.; Camuzat A.; Guerreiro R.; Bouya-Ahmed K.; Bras J.; Nicolas G.; Gabelle A.; Didic M.; De Septenville A.; Millecamps S.; Lenglet T.; Latouche M.; Kabashi E.; Campion D.; Hannequin D.; Hardy J.; Brice A.;
JAMA Neurol. 70:1403-1410(2013)
Cited for: INVOLVEMENT IN FTDALS3; VARIANTS FTDALS3 VAL-33; VAL-381; LEU-387 AND LEU-392; Structure of the ubiquitin-associated domain of p62 (SQSTM1) and implications for mutations that cause Paget's disease of bone.
Ciani B.; Layfield R.; Cavey J.R.; Sheppard P.W.; Searle M.S.;
J. Biol. Chem. 278:37409-37412(2003)
Cited for: STRUCTURE BY NMR OF 387-436; CHARACTERIZATION OF VARIANT LEU-392; DOMAIN; Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone.
Laurin N.; Brown J.P.; Morissette J.; Raymond V.;
Am. J. Hum. Genet. 70:1582-1588(2002)
Cited for: VARIANT PDB3 LEU-392; VARIANTS VAL-117 AND GLN-274; Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease.
Hocking L.J.; Lucas G.J.A.; Daroszewska A.; Mangion J.; Olavesen M.; Cundy T.; Nicholson G.C.; Ward L.; Bennett S.T.; Wuyts W.; Van Hul W.; Ralston S.H.;
Hum. Mol. Genet. 11:2735-2739(2002)
Cited for: VARIANT PDB3 LEU-392; 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; Identification of SQSTM1 mutations in familial Paget's disease in Australian pedigrees.
Good D.A.; Busfield F.; Fletcher B.H.; Lovelock P.K.; Duffy D.L.; Kesting J.B.; Andersen J.; Shaw J.T.E.;
Bone 35:277-282(2004)
Cited for: VARIANT PDB3 LEU-392; Two novel mutations at exon 8 of the Sequestosome 1 (SQSTM1) gene in an Italian series of patients affected by Paget's disease of bone (PDB).
Falchetti A.; Di Stefano M.; Marini F.; Del Monte F.; Mavilia C.; Strigoli D.; De Feo M.L.; Isaia G.; Masi L.; Amedei A.; Cioppi F.; Ghinoi V.; Maddali Bongi S.; Di Fede G.; Sferrazza C.; Rini G.B.; Melchiorre D.; Matucci-Cerinic M.; Brandi M.L.;
J. Bone Miner. Res. 19:1013-1017(2004)
Cited for: VARIANTS PDB3 LEU-392; VAL-404 AND ARG-425; Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration.
van der Zee J.; Van Langenhove T.; Kovacs G.G.; Dillen L.; Deschamps W.; Engelborghs S.; Matej R.; Vandenbulcke M.; Sieben A.; Dermaut B.; Smets K.; Van Damme P.; Merlin C.; Laureys A.; Van Den Broeck M.; Mattheijssens M.; Peeters K.; Benussi L.; Binetti G.; Ghidoni R.; Borroni B.; Padovani A.; Archetti S.; Pastor P.; Razquin C.; Ortega-Cubero S.; Hernandez I.; Boada M.; Ruiz A.; de Mendonca A.; Miltenberger-Miltenyi G.; do Couto F.S.; Sorbi S.; Nacmias B.; Bagnoli S.; Graff C.; Chiang H.H.; Thonberg H.; Perneczky R.; Diehl-Schmid J.; Alexopoulos P.; Frisoni G.B.; Bonvicini C.; Synofzik M.; Maetzler W.; vom Hagen J.M.; Schoels L.; Haack T.B.; Strom T.M.; Prokisch H.; Dols-Icardo O.; Clarimon J.; Lleo A.; Santana I.; Almeida M.R.; Santiago B.; Heneka M.T.; Jessen F.; Ramirez A.; Sanchez-Valle R.; Llado A.; Gelpi E.; Sarafov S.; Tournev I.; Jordanova A.; Parobkova E.; Fabrizi G.M.; Testi S.; Salmon E.; Stroebel T.; Santens P.; Robberecht W.; De Jonghe P.; Martin J.J.; Cras P.; Vandenberghe R.; De Deyn P.P.; Cruts M.; Sleegers K.; Van Broeckhoven C.;
Acta Neuropathol. 128:397-410(2014)
Cited for: INVOLVEMENT IN FTDALS3; VARIANTS FTDALS3 VAL-16; VAL-33; GLU-80; MET-90; TRP-107; ASN-129; CYS-212; VAL-219; PRO-226; LEU-228; THR-232; LYS-238 DEL; ASN-258; CYS-321; GLY-329; LEU-348; LEU-387; LEU-392 AND PRO-430; VARIANTS VAL-17; ARG-103; GLN-107; TYR-108; HIS-110; VAL-117; SER-118; GLY-119; SER-125; CYS-139; ILE-153; LEU-180; HIS-217; GLU-238; 265-SER-ARG-266 DELINS SER-ARG; ASP-274; ILE-278; VAL-308; LYS-319; GLY-334 DEL; THR-349 AND LEU-439;

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.