n structure/gene family structure and evolution)

To understand the structural, functional, and evolutionary relationships among the principal protein components of rat high density lipoprotein particles, we un- dertook a systematic comparative analysis of the primary structures of apolipoproteins (apo)-A-I, -A-IV, and -E. Hu- man apo-A-I and rat apo-A-IV have been shown previously to contain repeated sequences that presumably arose by intra- genic duplication of 11- or 22-amino acid amphipathic seg- ments. For apo-A-I, these segments are thought to be the structures responsible for lipid binding and activation of lec- ithin:cholesterol acyltransferase. From an analysis of the se- quence of a full-length cDNA clone, rat apo-A-I is shown to contain eight tandem repetitions of a 22-amino acid segment. However, compared with human apo-A-I, the rat protein has undergone three deletions, two of which involve multiple ami- no acids in the repeated sequence domain. This disruption of the periodic structure of the protein raises the possibility of species-specific variation in the ability of rat apo-A-I to inter- act with high density lipoproteins and activate lecithin:choles- terol acyltransferase. Statistical analysis of the structure and organization of repeated sequences in apo-A-I, -A-IV, and -E demonstrates that all three proteins are paralogous members of a dispersed gene family. Despite overall similarity in se- quence organization, different portions of these sequences have evolved at different rates. Diversification of a duplicated ancestral sequence has resulted in three lipid-binding proteins with distinct and shared functions.