Ortholog conservation:

The wild-type residue P1290 is highly conserved among the CFTR orthologs: 96% (48 / 50 CFTR orthologs)
The variant P1290T has been found among the CFTR orthologs with a low frequency: 4% (2 / 50 CFTR orthologs)

*AAPI: Alignment Average Percentage Identity
**AAPIR: Alignment Average Percentage Identity of the Region (20 residues surrounding position 1290). AAPIR appears in green if it is more than 10% compared to AAPI, in red if less than 10%.
Click here for more details on the alignment.

CYSMA's visualizing modules for Ortholog conservation:

⬇ Download the region alignment (50 residues, Fasta format)
⬇ Download the CFTR phylogenic tree

Display methods

Domain conservation:

The residue p.Pro1290 belongs to the domain NBD2.

1210

1443

NBD2: is the nucleotide binding domain 2, also called the ATP-binding cassette (ABC).
It contains the Walker A (P-loop) and Walker B motifs, the C-motif (also known as the signature sequence), the A-, D-, Q-, and H-loops.

	is the nucleotide binding domain 2, also called the ATP-binding cassette (ABC). It contains the Walker A (P-loop) and Walker B motifs, the C-motif (also known as the signature sequence), the A-, D-, Q-, and H-loops.

NBD2 of CF Transmembrane conductance Regulator domain alignment including p.Pro1290 residue.

***AAPID: Alignment Average Percentage Identity of the Domain (positions are indicated).
^!AAPIR: Alignment Average Percentage Identity of the Region (20 residues surrounding position 1290). AAPIR appears in green if it is more than 10% compared to AAPID, in red if less than 10%.

The wild-type residue P1290 belongs to the NBD2 domain and is conserved at 42.66% among the NBD2 homologs (305 / 715 NBD2 homologs)
The variant P1290T has been found among the NBD2 homologs with a high frequency: 12.17% (87 / 715 NBD2 homologs)

Divergencies show the amino acids which have been selected in the evolution. Residues present in more than 10% of the sequences are highlighted in blue.
Please note that CYSMA does not consider splicing alterations.
Refer to the Help page for more details.

CYSMA's visualizing modules for NBD2 domain conservation:

Display methods

Secondary structure analysis:

Residue p.Pro1290 is predicted to belong to a loop. Probability is 0.568.

Direct environment is as follow:

F	G	V	I	P1290	Q	K	V	F

Display methods

3D analysis:

Models provided and analysed by CYSMA 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.

Wild type and predicted mutant structures have been compared. You will find the results below.

• Overall quality of the structure:
  
  

  PDB template	Sequence identity*	MolProbity bad rotamers	MolProbity Ramachandran outliers	MolProbity Ramachandran favored
  5UAK	99.8 %	18/1313 - 1.37 %	17/1478 - 1.15 %	1360/1478 - 92.2 %

  
  
  

• Click on the MolProbity logo for complete details on the structure quality
  
  
  
  

• This model is made of 37 α helices and of 20 β strands (and is mainly composed of helices (739 residues in helices against 102 in strands, for a total of 1480 amino acids)).
  
  
• 3D structures predicts P1290 to be located in a loop (which confirms PsiPred prediction) and T1290 in a loop.
  
  
  



CYSMA's modules to download the 3D structures:



Chech 3D coverage of CFTR models ⬇ Download the wild-type 3D structure (PDB format) ⬇ Download the mutant 3D model (PDB format)





CYSMA's 3D Automatic Annotation:





WARNING!
The experimental 3D structure used for our predictions is the complete human CFTR structure which have been solved at a 3.7 Å resolution using cryo-electron microscopy (PDB: 5UAK; Liu et al. 2017).
The overall resolution is fairly low so the CYSMA's 3D Automatic Annotation pipeline might have missed some important structural effects.




• Replacement of a proline is likely to increase the flexibility of the region
  
  
• Solvent accessibility: the wild-type residue P1290 is predicted to be exposed, while the mutant residue P1290T is predicted to be buried, what could destabilize the domain
  
  
• The two residues have a different polarity, which could interfere with hydrogen-bonding capabilities
  
  
• Hydrogen bond network:
  

  P1290	T1290
  none	distance: 3.73 Å / angle: 2.33 rad between THR 1290 OG1 and VAL 1293 N distance: 2.94 Å / angle: 2.02 rad between THR 1290 OG1 and LYS 1292 O

  
  
  
• The mutant residue is predicted to form less hydrophobic interactions than the wild-type
  

  P1290	T1290
  4.44 Å between PRO 1290 CD and ILE 1289 CB 4.53 Å between PRO 1290 CD and VAL 1288 CB 4.14 Å between PRO 1290 CB and VAL 1288 CG1 4.63 Å between PRO 1290 CG and VAL 1288 CB	none

  
  
  

For hydrophobic effects, the important point is the number of residues involved more than the number of interactions.



• The mutant residue is not predicted to introduce steric clashes
  

  P1290	T1290
  2.97 Å between PRO 1290 CB and GLN 1291 N	3.04 Å between THR 1290 CB and GLN 1291 N

  
  
  

CYSMA's 3D visualizing module:



• If you want to investigate further the structures, you can use the JSmol applets of the wild-type (left) and mutant (right) structures.
  
  Click on the JSmol applets' link to hide it.
  You have a full access to Jmol commands with a simple right click on one applet.
  
  
  
  
  

  P1290 (wild-type)	T1290 (mutant)

  
                Slab       Spin on/off       Show measurements       Change background       Sharper/Faster                    

  
  JSmol Legends:
  The residue at the position 1290 is located in the center, labelled in yellow and surrounded by its neighboring residues (distance < 5 Å).
  Van der Waals contacts with the residue 1290 are represented by dotted lines.
  Amino acids involved in H-bonds with the residue 1290 are labelled in blue.
  Amino acids involved in steric clashes with the residue 1290 are labelled in red.

  
  Display JSmol complete legends

  The overall structure of the complete human CFTR is represented in ribbon diagrams (click on the Reset button to visualize the overall CFTR structure).
  The membrane-spanning domain MSD1 is represented in blue and MSD2 in light blue.The nucleotide-binding domain NBD1 is represented in orange, NBD2 in light salmon.The lasso domain is shown in red and the R domain in green.

  Display Molecular Modelling methods

  The 3D structures used in CYSMA are models based on the CFTR experimental 3D structure in the channel-closed conformation (PDB: 5UAK; resolution: 3.9 Å).
  In the wild-type model, the (missing) loops and the (missing) R domain were built de novo using the software Modeller. For the variant models, the point mutation (homology modelling) are made on the fly with Modeller (more). 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.
  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).
  Structural properties are calculated using an in-house developped program based for the USMA's 3D Automatic Annotation pipeline.

  Refer to the Help page for more details.

• SIFT prediction: variant P1290T is predicted to be tolerated (score: 0.12)


• PPH2 prediction: variant P1290T is predicted to be benign (score: 0.208)


• UNIPROT annotations
  

  The variation is not reported in Uniprot.

• Click on the LOVD picture to check if a variant is described at position 1290    
  
  
  
  



• Graphical display of the region at NCBI (including SNPs)



• CYSMA Report:

  
  

  Report for p.Pro1290Thr variant

  CFTR orthologs conservation	The wild-type residue P1290 is highly conserved among the CFTR orthologs: 96% (48 / 50 CFTR orthologs) The variant P1290T has been found among the CFTR orthologs with a low frequency: 4% (2 / 50 CFTR orthologs)
  NBD2 homologs conservation	The wild-type residue P1290 belongs to the NBD2 domain and is conserved at 42.66% among the NBD2 homologs (305 / 715 NBD2 homologs) The variant P1290T has been found among the NBD2 homologs with a high frequency: 12.17% (87 / 715 NBD2 homologs)
  Structural effects	Replacement of a proline is likely to increase the flexibility of the region Solvent accessibility: the wild-type residue P1290 is predicted to be exposed, while the mutant residue P1290T is predicted to be buried, which could destabilize the domain The two residues have a different polarity, which could interfere with hydrogen-bonding capabilities The mutant residue is predicted to form less hydrophobic interactions than the wild-type The mutant residue is not predicted to introduce steric clashes
  Allele frequency	The variant P1290T in gnomAD (123,136 exomes): 3.99e-06 ; variant P1290T in gnomAD (15,496 genomes): 3.19e-05 The variant P1290L in gnomAD (123,136 exomes): 1.20e-05
  Clinical significance	The variant P1290T has not been reported in ClinVar
  CFTR-France	The variant P1290T might correspond to: NM_000492.3:c.3868C>A, which is reported to be unclassified ( CFTR-France for more details)
  Additional resources	SIFT prediction: variant P1290T is predicted to be tolerated (score: 0.12) PPH2 prediction: variant P1290T is predicted to be benign (score: 0.208)