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Ortholog conservation Domain conservation Secondary structure 3D structure More Home

Analysis of p.(Gly4692Arg) variant, USH2A gene, usherin protein (5202 residues)

• Ortholog conservation:

  
  
  

  Number of sequences	AAPI*	AAPIR**	Number of divergencies	Number of mutant	Number of gaps	Conservation of G4692	Conservation - gap
  17	55.91%	41.51%	6 details	0 details	0 details	11 / 17 (64.71%)	11 / 17 (64.71%)

  
  
  

  Divergencies:

  Danio rerio - D	Gasterosteus aculeatus - N	Takifugu rubripes - N	Strongylocentrotus purpurat - T	Ciona intestinalis - V
  Ciona savignyi - T

  The mutant residue cannot be found in the alignment.

  There is no gap in the alignment.

  *AAPI: Alignment Average Percentage Identity
  **AAPIR: Alignment Average Percentage Identity of the Region (20 residues surrounding position 4692). AAPIR appears in green if it is more than 10% compared to AAPI, in red if less than 10%.

  You can check the AAPIRs compared with AAPI of the whole alignment by clicking here. The help page will tell you more.

  Display alignment

  Click on the alignment to zoom in and out.

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  Homo sapiens

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  Equus caballus

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  Canis familiaris

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  Cavia porcellus

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  Monodelphis domestica

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  Taeniopygia guttata

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  Gallus gallus

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  Danio rerio

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  Gasterosteus aculeatus

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  Takifugu rubripes

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  Strongylocentrotus purpurat

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  Ciona intestinalis

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  Ciona savignyi

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  Species color legend (basic classification):

  Great apes | Other monkeys | Prosimians | Other mammals | Lizards | Birds | Amphibians | Fishes | Insects | Nematods | Tunicates | Echinoderms

  Show Venn diagram of alignment

  Display WebLogo for the region

  Click on the top-left corner to enlarge.

  

  Display alignment phylogenetic tree

  Click on the top-left corner to enlarge.

  
  

  Download tree in Newick format (right-click on the link, and choose 'Save target as').

  Display region alignment (21 residues, Fasta format)

  Display methods

  Ortholog sequences have been selected from the Ensembl⁽¹⁾ and NCBI websites. Alignment has been performed with ClustalW⁽²⁾, version 1.83 or 2.0.7. Trees have been built using Phylogeny.fr ⁽³⁾, based on the alignments. Software used is PhyML 3.0 aLRT with default parameters. Pictures of trees have been made using Phylip at Mobyle. AAPI and AAPIR have been calculated thanks to Bioperl. WebLogos are drawn with WebLogo 3⁽¹⁴⁾

  Accession numbers

• Domain conservation:

  The residue belongs to the domain Fibronectin type-III 32.

  4633

  4730

  	fnIII repeats are made of ~ 100 residues and form beta-sandwiches. Their role in usherin is unknwon, but is likely to be crucial , as numerous deleterious missense variants are reported.

  
  
  
  
  

  Fibronectin type-III 32 of usherin domain alignment including p.G4692 residue.

  
  
  

  Number of sequences	AAPID*** (from aa 4633 to aa 4730)	AAPIR!	Number of divergencies	Number of mutant	Number of gaps	Conservation of G4692	Conservation - gap
  2036	17.77%	10.32%	1606 details	55	2	428 / 2036 (21.02%)	428 / 2034 (21.04%)

  
  
  

  Divergencies

  Residues present in more than 10% of the sequences are highlighted in blue.

  A - 8.79%	C - 1.92%	D - 2.31%	E - 2.36%	F - 0.54%	H - 1.18%	I - 4.42%	K - 2.50%	L - 5.70%	M - 0.44%
  N - 3.34%	P - 12.03%	Q - 1.57%	R - 2.70%	S - 9.68%	T - 7.66%	V - 10.17%	W - 0.25%	Y - 1.33%

  If we just consider Fibronectin type-III domain of usherin, we can add that:
  
  on 35 sequences, conservation is 15/35 (42.86%),
  or 15/34 (44.12%) if you do not take the gaps into account.

  ***AAPID: Alignment Average Percentage Identity of the Domain (positions are indicated).
  ^!AAPIR is here compared with AAPID.

  Show Venn diagram of alignment

  Display WebLogo for the region

  Click on the top-left corner to enlarge.

  

  Display complete alignment (Clustal format)

  Display region alignment (21 residues, Fasta format)

  Display methods

  Alignments have all been extracted from Prosite⁽⁴⁾, except alignment of vlgr1 calx-beta domains which comes from Pfam⁽⁵⁾. Pictures of proteins have been performed using MyDomains - Image Creator. WebLogos are drawn with WebLogo 3⁽¹⁴⁾

• Secondary structure analysis:

  Residu G4692 is predicted to belong to a loop. Probability is 0.936.

  Direct environment is as follow:

  L	I	Y	N	G4692	S	S	T	S

  
  
  

  Display methods

  Predictions of secondary structures have been made with PsiPred⁽⁹⁾ , version 2.5, using Protein Multiple Sequences Alignments as input, in order to increase the accuracy of the prediction. Amino acid frequencies have been calculated from a non redondant set defined by the RCSB. Details are provided here.

• 3D analysis:

  Models provided and analysed by USMA must be considered as predictions, therefore be careful when interpreting the results. All efforts have been made to build structures of quality, however, they are provided with NO WARRANTY as to their accuracy with the real biological molecules studied.

  Predicted wild type and mutant structures have been compared. You will find the results below. Please note that USMA's "3D engine" is unable to analyse interactions with non amino-acids molecules (e.g. ATP or Ca²⁺).

  • Quick assessment of the overall quality of the structure:
    
    

    PDB template	Sequence identity*	Molprobity bad rotamers	Molprobity Ramachandran outliers	Molprobity Ramachandran favored
    2EDX	25.2 %	1/101 - 1 %	2/114 - 1.8 %	108/114 - 94.7 %

    * between target and template

    Otherwise, see detailed Molprobity output

    
    
  • Download wild-type model (PDB format) or mutant prediction.
    
    
  • Check 3D coverage of usherin.
    
    
  • This model is made of 0 α helices and of 7 β strands (and is mainly composed of strands (0 residues in helices against 40 in strands, for a total of 116 amino acids)).
    
    
  • 3D model predicts G4692 to be located in a loop (which confirms PsiPred prediction) and R4692 in a loop.
    
    
    
  • Replacement of a glycine is likely to rigidify the local structure.
    
    
  • The wild type residue is predicted to be buried and the mutant residue to be exposed.
    
    
  • The 2 residues have a different polarity.
    
    
  • The two residues have different charges, which can interfere with ionic bonds or potential inter- or intra-molecular interactions.
    
    
  • The mutant residue is predicted to alter the hydrogen bond network.
    
    

    G4692	R4692
    none	distance: 2.99 Å / angle: 2.88 rad between NE and VAL 4667 O

    
    
    
  • The mutant residue is predicted to introduce steric clashes.
    
    

    G4692	R4692
    none	2.84 Å between CA and TYR 4670 CE1

    
    
    
  • Pictures:
    Click on the top-left corner to enlarge.
    Legend: non-covalent bonds/steric clashes: - - - - colors: - - - -: h-bonds, - - - -: ionic bonds, - - - -: hydrophobic interactions; - - - -:clashes.
    
    
    
    
  • If you are not satisfied with the pictures above, or just want to investigate further the structures, you can display the JSmol applet of the wild-type (left) and mutant (right) structures.
    
    Click on the JSmol applet's link to hide it.
    You have a full access to Jmol commands with a simple right click on one applet.
    
    
    
    
    

    G4692 (wild-type)	R4692 (mutant)

    
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    JSmol Legends:
    The residue at the position 4692 is located in the center, labelled in yellow and surrounded by its neighboring residues (distance < 5 Å).
    Amino acids involved in H-bonds with the residue 4692 are labelled in blue.
    Amino acids involved in steric clashes with the residue 4692 are labelled in red.

    Display methods

    All 3D structures except two for harmonin and sans, and myosin VIIa and sans used in USMA are predictions. They are build by homology, (more), using Domain Fishing⁽¹⁵⁾ or Atome 2⁽²⁵⁾ for template recognition, modeller⁽¹⁶⁾ for model building and mutation, and PyMOL⁽¹⁷⁾ and Jmol⁽¹⁸⁾ for visualisation. Each structure has been assessed with MolProbity⁽¹⁹⁾. Msms⁽²⁰⁾ is used to calculate solvent accessibility, and STRIDE⁽²¹⁾ (plus stride2pdb) for secondary structure assignment. When necessary, SCWRL4⁽²²⁾ was used to refine side chains conformations.
    Secondary structure analyses in 3D models uses side chain interaction energies reviewed in ⁽²³⁾, as well as amino-acids propensities for N-caps, N1-N3, helix middle, C3-C1 and C-caps extracted from ⁽²⁴⁾(PDB values).

• Additional ressources:

  
  
  
  • UNIPROT annotations
    

    The variation is not reported in Uniprot.

  • Click on the LOVD picture to check if a variant is described at position 4692    
    
    
    
    
  • Graphical display of the region at NCBI (including SNPs)

See accession numbers of sequences used or references.

Execution time: 3 wallclock secs ( 0.77 usr 0.01 sys + 1.57 cusr 0.58 csys = 2.93 CPU)