Low folding propensity and high translation efficiency distinguishin vivosubstrates of GroEL from otherEscherichia coliproteins

Abstract

Motivation: Theoretical considerations have indicated that the amount of chaperonin GroEL in Escherichia coli cells is sufficient to fold only $2-5% of newly synthesized proteins under normal physiological conditions, thereby suggesting that only a subset of E.coli proteins fold in vivo in a GroEL-dependent manner. Recently, members of this subset were identified in two independent studies that resulted in two partially overlapping lists of GroEL-interacting proteins. The objective of the work described here was to identify sequence-based features of GroEL-interacting proteins that distinguish them from other E.coli proteins and that may account for their dependence on the chaperonin system. Results: Our analysis shows that GroEL-interacting proteins have, on average, low folding propensities and high translation efficiencies. These two properties in combination can increase the risk of aggregation of these proteins and, thus, cause their folding to be chaperonin-dependent. Strikingly, we find that these properties are absent in proteins homologous to the E.coli GroEL-interacting proteins in Ureaplasma urealyticum, an organism that lacks a chaperonin system, thereby confirming our conclusions.

What distinguishes GroEL substrates from other Escherichia coli proteins?

“…These observations are also consistent with the results of Tartaglia et al. [15] and those of another study that showed that GroEL substrates have lower folding propensities compared with GroEL‐independent proteins [21]. Folding propensity was determined in the Noivirt‐Brik et al.…”

“…Fischer’s exact test was used to test whether the overlaps are statistically significant. The P ‐value for an overlap of 80 proteins (an overlap of 136 has been reported previously [21] when homologs were included) between classes I, II and III [12] when combined and the set identified by Chapman et al. [14] is < 10 −33 .…”

Physicochemical Determinants of Chaperone Requirements

“…Our results (Figs. 1 and 2), together with complementary recent studies, 39,40 provide evidence that such a link indeed exists. We have exploited the relationships between these quantities (arrows A, B and C in Fig.…”

GroEL Can Unfold Late Intermediates Populated on the Folding Pathways of Monellin

“…Perhaps the best-characterized molecular chaperone is the prokaryotic chaperonin GroEL, which, together with its cochaperonin cohort GroES, facilitates the folding of many proteins. [1][2][3][4][5][6] The roles played by such chaperones are even more crucial when the cell experiences stress, when even those proteins that can otherwise fold by themselves fold with decreased efficiency. [7][8][9] The primary role played by GroEL appears to be to associate reversibly with folding intermediates that would otherwise associate irreversibly with each other through exposed hydrophobic surfaces and, thereby, aggregate.…”

“…6,[12][13][14][15] In fact, GroEL appears to have evolved to become a universal chaperone that can bind to different nonnative conformations of many different proteins, irrespective of their native structures. 12,[16][17][18] It can bind to many of the intermediates that accumulate on the folding pathways of proteins, including unfolded forms, early unstructured intermediates, molten globule intermediates, late structured intermediates, and native-like states.…”