Mapping the chemical and sequence space of the ShKT superfamily
journal contributionposted on 2021-01-06, 05:40 authored by Thomas ShafeeThomas Shafee, Michela L Mitchell, Raymond S Norton
© 2019 Elsevier Ltd
The ShKT superfamily is widely distributed throughout nature and encompasses a wide range of documented functions and processes, from modulation of potassium channels to involvement in morphogenesis pathways. Cysteine-rich secretory proteins (CRISPs)contain a cysteine-rich domain (CRD)at the C-terminus that is similar in structure to the ShK fold. Despite the structural similarity of the CRD and ShK-like domains, we know little of the sequence-function relationships in these families. Here, for the first time, we examine the evolution of the biophysical properties of sequences within the ShKT superfamily in relation to function, with a focus on the ShK-like superfamily. ShKT data were sourced from published sequences in the protein family database, in addition to new ShK-like sequences from the Australian speckled anemone (Oulactis sp.). Our analysis clearly delineates the ShK-like family from the CRDs of CRISP proteins. The four CRISP subclusters separate out into the main phyla of Mammalia, Insecta and Reptilia. The ShK-like family is in turn composed of seven subclusters, the largest of which contains members from across the eukaryotes, with a continuum of intermediate properties. Smaller sub-clusters contain specialised members such as nematode ShK-like sequences. Several of these ShKT sub-clusters contain no functionally characterised sequences. This chemical space analysis should be useful as a guide to select sequences for functional studies and to gain insight into the evolution of these highly divergent sequences with an ancient conserved fold.
The authors acknowledge Dr. Rodrigo A. V. Morales and Edward Airey for their contribution to the preparation of sequences used in the analysis. This project was funded in part by ARC linkage grant LP150100621. M.L.M acknowledges an Australian Government Research Training Program Scholarship, Monash Medicinal Chemistry Faculty Scholarship and Monash University - Museum Victoria Scholarship top-up. R.S.N acknowledges fellowship support from the Australian National Health and Medical Research Council.
ARC | LP150100621
Australian Government Research Training Program Scholarship
Monash Medicinal Chemistry Faculty Scholarship
Australian National Health and Medical Research Council
Monash University - Museum Victoria Scholarship
Pagination8p. (p. 95-102)
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Science & TechnologyLife Sciences & BiomedicinePharmacology & PharmacyToxicologyShKTCysteine-rich peptideDisulfide-rich proteinPeptide evolutionPeptide structureSequence analysisPOTASSIUM-CHANNEL TOXINCRYSTAL-STRUCTURER PACKAGEPROTEINDOMAINPEPTIDEINHIBITORMETALLOPROTEINASEEVOLUTIONGENOMECnidarian VenomsCluster AnalysisSequence Analysis, ProteinEvolution, MolecularPrincipal Component AnalysisModels, MolecularProtein Domains