Generation of Protein Isoform Diversity by Alternative Splicing: Mechanistic and Biological Implications

SELECTION OF SPLICE SITES 209 MODES OF ALTERNATIVE SPLICING . . . . . . . . .. . . . . . . . . . ... . ...... . . .. . . . . . ...... . . . . . . . . . . . . . . . . . 218 Combinatorial Exons . . . . . . . . ... . . . . . . . . .. .. ...... . . ......... . . . . ....... . . . . . . ... .... . . . . . . .... .... . . . . . . ......... . . . 2 19 Mutually Exclusive Exons . . . . ..... . . . . . . . . ..... ..... ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 Internal Donor and Acceptor Sites ...... . . . . . . . . . . . . . . . . . . . . . . .. . ..... . . . . . . ......... . . . . . . . ..... . . 220 Retained Introns 220 Multiple 5' and 3' Terminal Exons . . . . ... ..... . . . . . ........ . . . ......... ... . . . . . . . . . . . . . . . . . . . . . . . . . .... . . . . . . . 220 REGULATORY MECHANISMS OF ALTERNATIVE SPLICING . . . .... . . . . . . .. . ..... . . . . . ....... . . . . . . ... 221 Possible Categories of Mechanisms . . . . . . ... . .. . .. ......... . . . .. . ... .. . ... . . . . .. . . . . .. . . . .. . . . . . . 221 Cis-Regulated Splice-Site Selection ... . . . .. . . ...... . . . . . . . . . . . ......... . ... ...... . . . . . . . . . .... . . . . 221 Cisand Trans-Regulated Splice-Site Selection .... . . . . . . . . . .. .. . . . . . . . . . . . .. . . . . . . . . . . .. ........ . . . . . . 226 Trans-Regulated Splice-Site Selection . . . .... . . . ... ........ . . . . ....... . . . . . . . ...... .... . . ....... . 230 Processivity and Directionality of Alternative Splicing ... . . . . . . . ......... .. . 232 BIOLOGICAL IMPLICATIONS OF ALTERNATIVE SPLICING ... ........ ........ .. . . . . . ... ... .. . . ... . . . . .. . . . ... . 232 Alternative Splicing Is a Mechanism that Generates Families of Proteins with Variable and Constant Domains... . . . . . . . . .... . . . . . . . ..... . . . . . . . . . . . . . . . . . . . . . .. . .. . . . . . . . . . . . . 232 Alternative Splicing Is an Efficient and Reversible Posttranscriptional Mechanism for Performing Isoform Switches . . . .. .... . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . ... . .. . . . . . . . . . . . . . . . . . 234 Alternative Splicing May Represent a Primitive Mode of Splicing important for Gene Evolution.. . . . . . . . . . . . . . . . .. ... . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . ......... . . ..... . . . . . . . . . . . . . . . . . . . . . 235