UniProtKB/Swiss-Prot Q96CV9: Variant p.Glu50Lys

Optineurin
Gene: OPTN
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Variant information Variant position:

50 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 Glutamate (E) to Lysine (K) at position 50 (E50K, p.Glu50Lys). 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 acidic (E) to large size and basic (K) 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
Variant description:

In GLC1E; selectively promotes cell death of retinal ganglion cells probably by inducing TBC1D17-mediated inhibition of autophagy; affects Rab8-mediated endocytic trafficking; no effect on interaction with TBC1D17; increases colocalization with TBC1D17 and Rab8; increases interaction with TFRC and impairs its endocytic recycling; increases interactions with TBK1; decreases self-association; disturbs transition from the ER to Golgi; no effect on ubiquitin-binding; increases interaction with RAB8A as shown by immunoprecipitation in transfected HeLa cells, although other assays in yeast and mice show loss of direct interaction, it has been proposed that the variant might abolish direct interaction with Rab8 and enhance indirect interaction, hence altering the functional positioning of the molecules in the complex in such a way that it leads to constitutive or increased inactivation of Rab8 by TBC1D17. Any additional useful information about the variant.
Other resources:

Links to websites of interest for the variant.

Variant rs28939688 [ dbSNP | Ensembl ]

Sequence information Variant position:

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

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

PNLDTFTPEELLQQMKELLT E NHQLKEAMKLNNQAMKGRFE 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                         PNLDTFTPEELLQQMKELLTENHQLKEAMKLNNQAMKGRFE

Rhesus macaque                PNLDTFTPEELLQQMKELLTENHQLKEAMKLNNQAMKGRFE

Mouse                         PSLDTFTPEELLQQMKELLVENHQLKEAMKLNNQAMKGRFE

Rat                           PNLDTFTPEELLQQMKELLVENHQLKEAMKLNNQAMKGRFE

Pig                           PNLDTFTPHELLQQMRELLIENHQLKEAMKLNNQAMKGRFE

Chicken                       PTLSTYTPEEMVQQMKELITENNELKEAMKLHNQAMKDRYE

Xenopus laevis                DALSMKNDAEMLEQIKQLLMENNNLKETMKQMNQEMKERLE

Zebrafish                     ------SLEETLQQMNTLIKENRDLKEALKQTNLSMKERFE

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 – 577	Optineurin
Coiled coil	38 – 170
Alternative sequence	1 – 57	Missing. In isoform 3.
Mutagenesis	50 – 50	E -> K. No effect on retinal ganglion cell death, decreased interaction with TFRC, loss of localization to recycling endosomes, loss of ubiquitin-binding; when associated with N-474.
Helix	37 – 98

Literature citations
Adult-onset primary open-angle glaucoma caused by mutations in optineurin.
Rezaie T.; Child A.; Hitchings R.; Brice G.; Miller L.; Coca-Prados M.; Heon E.; Krupin T.; Ritch R.; Kreutzer D.; Crick R.P.; Sarfarazi M.;
Science 295:1077-1079(2002)
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1); FUNCTION; SUBCELLULAR LOCATION; TISSUE SPECIFICITY; VARIANTS GLC1E LYS-50 AND GLN-545; VARIANTS LYS-98; SER-201; HIS-213; ARG-216 AND PRO-357; Regulation of endocytic trafficking of transferrin receptor by optineurin and its impairment by a glaucoma-associated mutant.
Nagabhushana A.; Chalasani M.L.; Jain N.; Radha V.; Rangaraj N.; Balasubramanian D.; Swarup G.;
BMC Cell Biol. 11:4-4(2010)
Cited for: FUNCTION; SUBCELLULAR LOCATION; INTERACTION WITH TFRC; UBIQUITIN AND RAB8A; MUTAGENESIS OF GLU-50 AND ASP-474; CHARACTERIZATION OF VARIANT GLC1E LYS-50; Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice.
Chi Z.L.; Akahori M.; Obazawa M.; Minami M.; Noda T.; Nakaya N.; Tomarev S.; Kawase K.; Yamamoto T.; Noda S.; Sasaoka M.; Shimazaki A.; Takada Y.; Iwata T.;
Hum. Mol. Genet. 19:2606-2615(2010)
Cited for: CHARACTERIZATION OF VARIANT GLC1E LYS-50; Optineurin mediates a negative regulation of Rab8 by the GTPase-activating protein TBC1D17.
Vaibhava V.; Nagabhushana A.; Chalasani M.L.; Sudhakar C.; Kumari A.; Swarup G.;
J. Cell Sci. 125:5026-5039(2012)
Cited for: FUNCTION; SUBCELLULAR LOCATION; INTERACTION WITH RAB8A AND TBC1D17; CHARACTERIZATION OF VARIANT GLC1E LYS-50; E50K-OPTN-induced retinal cell death involves the Rab GTPase-activating protein, TBC1D17 mediated block in autophagy.
Chalasani M.L.; Kumari A.; Radha V.; Swarup G.;
PLoS ONE 9:E95758-E95758(2014)
Cited for: SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANT GLC1E LYS-50; MUTAGENESIS OF GLU-50 AND ASP-474; Enhanced optineurin E50K-TBK1 interaction evokes protein insolubility and initiates familial primary open-angle glaucoma.
Minegishi Y.; Iejima D.; Kobayashi H.; Chi Z.L.; Kawase K.; Yamamoto T.; Seki T.; Yuasa S.; Fukuda K.; Iwata T.;
Hum. Mol. Genet. 22:3559-3567(2013)
Cited for: SELF-ASSOCIATION; SUBCELLULAR LOCATION; INTERACTION WITH TBK1; CHARACTERIZATION OF VARIANT GLC1E LYS-50; A glaucoma-associated mutant of optineurin selectively induces death of retinal ganglion cells which is inhibited by antioxidants.
Chalasani M.L.; Radha V.; Gupta V.; Agarwal N.; Balasubramanian D.; Swarup G.;
Invest. Ophthalmol. Vis. Sci. 48:1607-1614(2007)
Cited for: CHARACTERIZATION OF VARIANT GLC1E LYS-50;

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.