From Protein Structure to Function with Bioinformatics.pdf

286 J.D. Watson and J.M. ThorntonFig. 11.5 Monomer of AF0491 protein from A. fulgidus, a homologue of the human Shwachman-Bodian-Diamond syndrome (SBDS) protein. The three domains are coloured orange, green andpurple in order from the N-terminus to the C-terminus2005) is widely used in DNA binding and has also been identified in RNA-bindingproteins (Schade et al. 1999). In this case however, the surface of AF0491 does nothave the expected general basic character so is not expected to have a nucleic acidbinding function, rather it is suggested by the authors that part of this domain mayactually be involved in protein-protein interactions.The N-terminal domain is a novel fold and is also where most of the diseaselinkedmutations are identified in SBDS patients. A subsequent structural searchidentified this new fold in a yeast protein, YHR087W. The identification of thisyeast structural homologue allowed for additional experiments not possible withthe human protein. Experimental investigation of the SBDS structural andsequence homologues (YHR087W and YLR022C respectively) indicate links toRNA metabolism. Strains lacking the YLR022C gene are not viable but TAPtaggedYLR022C co-purified with numerous ribosomal proteins and proteinsassociated with rRNA processing. Strains lacking YHR087W are viable, so astrain deleted for YHR087W was crossed with a miniarray of 383 other deletionstrains, each lacking a protein implicated in RNA metabolism. A number of thesecombinations showed substantial lethality and all the genetic interactions identifiedfor YHR087W support a role for the protein in RNA processing. Although thedata link the SBDS protein to ribosomal biogenesis, the specific role of SBDS inthe pathway remains to be determined, and the fundamental differences betweenbacterial ribosomal biogenesis (Lecompte et al. 2002) and that of Archaea andEukarya mean that any functional inferences must be treated with care. However,this is an example where the structural determination of a bacterial homologue ofa human protein has identified additional homologues in yeast useful for experimental-basedinference of function.