Proposed pathway for the appearance of ABC uptake systems Our proposed pathway for the appearance of ABC uptake systems of differing topologies is shown in Figure 14. A primordial 3 TMS porter duplicated internally to give rise to a 6 TMS

porter [1], and this 6 TMS porter again duplicated to give rise to a 12 TMS porter. Possibly a primordial 4 TMS porters could have arisen via either of two routes: first, one TMS might have been added at the C-terminus of the three TMS precursor, or second, the six TMS porter could have lost two TMSs at its C-terminus. Although speculation in view of the uncertainties of the topological predictions, the second route is favored (see Results). Further, one TMS could have been added between the 5th and 6th TMSs of a 6 TMS porter to give rise to a 7 TMS porter; however, the occurrence of this 7 TMS topological type is less likely Selumetinib and may be due to erroneous predictions by the HMMTOP and TMHMM programs. Figure 14 Proposed evolutionary pathway and primordial Adriamycin solubility dmso sequences of the different topological types of ABC uptake systems. A (left). The proposed evolutionary pathway for the appearance

of present-day ABC uptake systems. B (right). Presumed primordial or intermediate sequences and representative examples of the different topological types of ABC transmembrane porter proteins. Starting with similar 3 TMS internally duplicated primordial 6 TMS porters, one TMS was apparently deleted at the N-terminus to gives rise to some of the current 5 TMS porters. In a distinct event, a 6 TMS porter may have lost a C-terminal TMS to give rise

to a different 5 TMS type of porter. These two events, giving rise to two recognizably distinct 5 TMS homologues, undoubtedly occurred independently of each other as indicated in Figure 14. Although likely, it is not absolutely certain that a 6 TMS protein gave rise to the C-terminally truncated 5 TMS homologue in a single step. Possibly, the 5 TMS protein arose in two steps via a 4 TMS intermediate. Four-TMS ABC uptake porter proteins could have existed [12] as their 8 TMS duplicated products may exist today, but this suggestion is not well documented. Because TMSs 5 in the 5 TMS homologues do not show appreciable sequence similarity with TMS 5 in Cyclin-dependent kinase 3 the 6 TMS proteins (Figure 10), we cannot securely distinguish the route from a 6 TMS or a 4 TMS precursor. However, the simpler one step pathway is favored. Intragenic duplication of a 5 TMS homologue gave rise to the 10 TMS porters, and the 10 TMS porter duplicated internally to give rise to the 20 TMS porters. Aligning the first ten TMSs with the second ten TMSs of the twenty TMS porters yielded high comparison scores (≥ 33 S.D.), indicating that this intragenic duplication event happened relatively recently in evolutionary time.