Introduction
Major Instrinsic Proteins (MIPs) are members of the Major Intrinsic Proteins(MIP) superfamily that are involved in the transport of water and other neutral solutes across lipid bilayers. They are present in all forms of life from bacteria to higher organisms. In humans, 13 MIPs have been identified from AQP0 to AQP12 and can be broadly classified into three groups:
- Orthodox aquaporins - Channels which are strictly involved in the transport of water
AQP0, AQP1, AQP2, AQP4, AQP5
- Aquaglyceroporins - Channels which are involved in the transport of glycerol, water and other neutral solutes.
AQP3, AQP7, AQP9, AQP10
- S-Aquaporins - Channels which are expressed in the intracellular membranes
AQP6, AQP8, AQP11, AQP12
Certain mutations or variations in these aquaporins impair their transport properties and have been implicated in multiple disease conditions such as cataracts(AQP0) and Nephrogenic Diabetes Insipidus (AQP2).
Structure: In biological conditions, aquaporins assemble as tetramers with each monomer being a functional unit with a unique hourglass fold. Each monomer consists of six transmembrane helices (TM1 - TM6) and two half helices (LB and LE).
About dbAQP-SNP
dbAQP-SNP contains the following information on 2,978 Single Nucleotide Polymorphisms (SNPs) resulting in missense variations identified in human aquaporins.
- The variation in the codon of mRNA and the resulting variation in the protein sequence.
- Generic numbers for the residues in the transmembrane segments and half helices.
- The occurrence of the residue in the structure of the aquaporin. Further information regarding the classification is provided in the following section.
- Pathogenicity of the variation and the implicated diseased condition.
The database can be searched and filtered through the search options described below.
Search options
Two types of search options are available in dbAQP-SNP - Keyword Search and Advanced search.
- Keyword search
A single word or multiple words (each string separated by "|") can be used to search the database. The results matching any of the strings will be displayed in the Results page. Phrase search can also be performed by using the complete phrase without the use of "|".
- Advanced search
Advanced search can be used to filter results according to the following criteria:
- Protein
- Occurrence of the residue in the structure
- Disease caused by the variation
- Variations in NPA motifs and the Ar/R selectivity filter
- Reference residues - residues in the reference sequence and their groups
- Variant residues and their groups
- Results: The results matching the queries in both the keyword and advanced search contain the information. These results can be downloaded in a .csv file using the Download option.
- Details: Summary and further information on each entry in the results page can be accessed by clicking on its dbAQP-SNP ID.
Naming and grouping convention
SNPs resulting in a single amino variation in human aquaporins were collected from dbSNP. The pathogenicity of the variations was attributed with the data collected from OMIM.
Amino acid residues are classified into 6 groups according to their size and chemical properties:
- Small and Weakly polar (Gly, Ala, Cys, Ser, Thr)
- Aliphatic Hydrophobic (Val, Leu, Ile, Met)
- Charged (Asp, Glu, His, Lys, Arg)
- Neutral Polar (Asn, Gln)
- Aromatic (Phe, Tyr, Trp)
- Proline (Pro)
The occurrence of each residue in the transmembrane segments and the half helices is classified into atleast one of the following groups :
- Channel facing
- Helix - helix interface
- Monomer - monomer interface
- Lipid facing
- Exposed to cytoplasm
- Exposed to the extracellular environment
For making the above classification, experimentally determined structures - AQP1 (PDB ID - 1FQY); AQP2(PDB ID - 4NEF); AQP4(PDB ID - 3GD8); AQP5(PDB ID - 3D9S); AQP7(PDB ID - 6QZI); AQP10(PDB ID - 6F7H), and modelled structures for the rest from MIPModDB were aligned. The membrane positioning for these structures was determined using PPM server.
Generic numbering scheme: Generic numbers to compare residue positions from different structures are attributed to the residues according to the scheme proposed in Gupta A.B., et. al.