An Greatly Expanded CATH-Gene3D with Functional Fingerprints to Characterise Proteins

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There are millions of proteins being sequenced which have no known function. New CATH methods will predict their functions. Whilst other resources do also predict function, CATH-Gene3D (referred to below as CATH) provides unique information on structurally conserved features linked to function. Structure data reveals how proteins perform their function and why the function changes if the protein is modified by mutations or other genetic variations. Protein function information is key to understanding biological systems and by extension drug design, protein engineering and disease.CATH is a world leading resource that classifies proteins evolved from the same ancestral protein, into evolutionary families. Currently, CATH classifies 15 million protein domains into 2600 families. Family data is valuable because evolutionary relatives (called homologues) tend to have similar 3D structures and perform similar functions. Thus the benefit of CATH is the ability to infer properties between homologues.This is important because of the millions of proteins currently known (>20 million) less than 5% have experimentally determined functions. Even in the organism of greatest interest to us, human, <10% of proteins have known functions. Because it can be slow and very expensive to characterise proteins it will not be possible to experimentally study all these proteins. Therefore, biologists use CATH to predict the function of a protein based on the family to which it belongs.Another fact is that proteins are made up of 'domains' - on average two per protein. These are independently folded entities that act together to confer the function of the whole protein. CATH classifies proteins at the level of the domain and currently classifies ~70% of domains found in nature. Domains are the building blocks of proteins - a few thousand of them are combined in different ways to give the 20 million proteins, or more, in nature. Our group develops methods for predicting domain functions. This allows functions of whole proteins to be deduced from the functions of their constitutive domains. Thus functions can be suggested for proteins made from any combination of domains.CATH uses information on the 3D structure of the domain to give more accurate family classifications, as structure is more highly conserved, during evolution, than the sequence. Even more important - structure can reveal how the protein performs its function and whether the protein loses its function if a mutation occurs at a particular site.We will expand CATH by 100%. Since manual validation is very time consuming, we will develop better methods for automatically recognising distant homologues. We will continuously release data (CATH-B), prior to manual curation, so that biologists can benefit from the information much sooner.We will collaborate with the other major structure classification SCOP to develop common classification strategies and provide complementary information on families.We will improve the accuracy of functional inheritance across a family. We need to do this because in some families, especially those occurring more frequently in nature, the functions can change in some relatives.We will improve accuracy by characterising important positions in the domain, conserved across functionally similar relatives. We can build patterns of these positions to recognise other domains sharing such patterns and likely to have similar functions.We will make it easy for biologists to use our web search tool to determine if a protein belongs to one of these functional families. We will set this up on the Cloud so that biologists can quickly search CATH with the massive datasets they obtain using new sequencing technologies. These technologies capture proteins expressed under different conditions. Our web pages will report their functions and variations in the protein which could modify function causing disease