UniProtKB/Swiss-Prot Q9C000 : Variant p.Pro1214Arg
NACHT, LRR and PYD domains-containing protein 1
Gene: NLRP1
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Variant information
Variant position:
1214
The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant:
LP/P [Disclaimer : Variants classification is intended for research purposes only, not for clinical and diagnostic use . The label disease variant is assigned according to literature reports on probable disease-association that can be based on theoretical reasons. This label must not be considered as a definitive proof for the pathogenic role of a variant. ]
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 Arginine (R) at position 1214 (P1214R, p.Pro1214Arg).
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 (P) to large size and basic (R)
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 AIADK; decreased interaction with DPP9, leading to increased inflammasome activity.
Any additional useful information about the variant.
Other resources:
Links to websites of interest for the variant.
Sequence information
Variant position:
1214
The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length:
1473
The length of the canonical sequence.
Location on the sequence:
LEKPARVELHHIVLENPSFS
P LGVLLKMIHNALRFIPVTSV
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 LEKPARVELHHIVLENPSFSP LGVLLKMIHNALRFIPV-TSV
Zebrafish LESVELTRFHAKILQ-PMFSP KTVLVKL------GIPVKVH
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 – 1473
NACHT, LRR and PYD domains-containing protein 1
Chain
1213 – 1473
NACHT, LRR and PYD domains-containing protein 1, C-terminus
Domain
1079 – 1364
FIIND
Region
1213 – 1364
UPA
Mutagenesis
1211 – 1211
S -> A. Partial loss of autocatalytic processing and of IL1B release.
Mutagenesis
1212 – 1212
F -> A. Complete loss of autocatalytic processing and of IL1B release.
Mutagenesis
1213 – 1213
S -> A. Complete loss of autocatalytic processing and of IL1B release. Autocatalytic processing cannot be restored by treatment with hydroxylamine. Abolished interaction with DPP9. Loss of activation by dsRNA or positive-strand RNA virus.
Mutagenesis
1213 – 1213
S -> C. Complete loss of autocatalytic processing, which can be restored by treatment with hydroxylamine.
Mutagenesis
1214 – 1214
P -> A. Partial loss of autocatalytic processing (50%) and of IL1B release (50%).
Literature citations
Human DPP9 represses NLRP1 inflammasome and protects against autoinflammatory diseases via both peptidase activity and FIIND domain binding.
Zhong F.L.; Robinson K.; Teo D.E.T.; Tan K.Y.; Lim C.; Harapas C.R.; Yu C.H.; Xie W.H.; Sobota R.M.; Au V.B.; Hopkins R.; D'Osualdo A.; Reed J.C.; Connolly J.E.; Masters S.L.; Reversade B.;
J. Biol. Chem. 293:18864-18878(2018)
Cited for: FUNCTION; ACTIVITY REGULATION; SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANT AIADK ARG-1214;
DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation.
Hollingsworth L.R.; Sharif H.; Griswold A.R.; Fontana P.; Mintseris J.; Dagbay K.B.; Paulo J.A.; Gygi S.P.; Bachovchin D.A.; Wu H.;
Nature 592:778-783(2021)
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (2.90 ANGSTROMS) IN COMPLEX WITH DPP9; FUNCTION; ACTIVITY REGULATION; INTERACTION WITH DPP9; MUTAGENESIS OF 1193-LEU-LEU-1194; SER-1213; HIS-1276; LYS-1277 AND GLU-1322; CHARACTERIZATION OF VARIANT AIADK ARG-1214;
A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis).
Grandemange S.; Sanchez E.; Louis-Plence P.; Tran Mau-Them F.; Bessis D.; Coubes C.; Frouin E.; Seyger M.; Girard M.; Puechberty J.; Costes V.; Rodiere M.; Carbasse A.; Jeziorski E.; Portales P.; Sarrabay G.; Mondain M.; Jorgensen C.; Apparailly F.; Hoppenreijs E.; Touitou I.; Genevieve D.;
Ann. Rheum. Dis. 76:1191-1198(2017)
Cited for: INVOLVEMENT IN AIADK; VARIANTS AIADK TRP-726 AND ARG-1214;
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.