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Title: The SAP domain : a modular approach to protein structure and function
Author: Jacobsen, Julius Octavius Bülow
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2004
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The domain is the conserved functional unit of proteins. Domains fold and function independently of each other with combinations of various domains allowing proteins of differing functions to be formed through evolution. A domain-based approach to structural genomics can afford maximum genomic and cross-genomic coverage due to this conservation of structure and function. In this study we have used this approach to probe the structure, folding and function of a newly defined domain- the SAP domain. SAP domains are found in many eukaryotic nuclear proteins involved in diverse nuclear processes. These range from transcriptional regulation, ubiquitination, SUMOylation, DNA repair, pre-mRNA splicing, mRNA export to DNA replication and chromatin remodelling. SAP domain proteins are also implicated in retroviral integration of HIV, various leukaemias and juvenile arthritis. We have determined the solution structure of the domain, which we use as the basis for the project. The structure showed that the domain has a novel fold that revealed little in the way of functional information. Using spectroscopic and kinetic methods we probed the thermal stability of the domain and determined its folding rate in comparison to a structurally similar DNA-binding domain. We investigated the structural basis of DNA recognition by the domain and discovered that it had little sequence specificity and appeared to preferentially bind distorted DNA structures. From this data we propose a model for the mode of DNA binding by the domain. As a test of in vivo function proposed from the results of the in vitro work, we performed transient transfections of the SAP domain and a mutant fused to a fluorescent protein in cultured cells.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available