The Protein Chaperone HSP90 Can Facilitate the Divergence of Gene Duplicates

Abstract

The heat-shock protein 90 (HSP90) acts as a chaperone by ensuring proper maturation and folding of its client proteins. The HSP90 capacitor hypothesis holds that interactions with HSP90 allow proteins to accumulate mutations while maintaining function. Following this logic, HSP90 clients would be predicted to show relaxed selection compared with nonclients. In this study, we identify a new HSP90 client in the plant steroid hormone pathway: the transcription factor BES1. Its closest paralog, BZR1, is not an HSP90 client. This difference in HSP90 client status in two highly similar proteins enabled a direct test of the capacitor hypothesis. We find that BES1 shows relaxed selection compared to BZR1, hallmarks of neo-and subfunctionalization, and dynamic HSP90 client status across independent evolutionary paths. These results suggested that HSP90's influence on gene evolution may be detectable if we compare gene duplicates because duplicates share most other properties influencing evolutionary rate that might otherwise conceal the chaperone's effect. We test this hypothesis using systematically identified HSP90 clients in yeast and observe a significant trend of HSP90 clients evolving faster than their nonclient paralogs. This trend was not detected when yeast clients and nonclients were compared without considering paralog status. Our data provide evidence that HSP90 influences selection on genes encoding its clients and facilitates divergence between gene duplicates.T HE phenotypic capacitor heat-shock protein 90 (HSP90) is thought to influence evolutionary processes through its ability to both conceal and release genetic variation (Rutherford and Lindquist 1998;Queitsch et al. 2002;Yeyati et al. 2007;Jarosz and Lindquist 2010). Perturbation of this conserved and essential chaperone reveals cryptic genetic and epigenetic variation in flies, plants, fish, and yeast (Rutherford and Lindquist 1998;Queitsch et al. 2002;Sollars et al. 2003;Yeyati et al. 2007;Jarosz and Lindquist 2010). In worms, HSP90 affects the penetrance of partial loss-of-function mutations (Burga et al. 2011). As expected under the capacitor hypothesis, worms with naturally lower HSP90 levels show significantly higher mutation penetrance (Casanueva et al. 2012). HSP90-dependent variation can be revealed by moderate environmental stress alone, providing a plausible release mechanism for this concealed variation in nature (Rutherford and Lindquist 1998;Queitsch et al. 2002;Jarosz and Lindquist 2010). We showed previously that HSP90-dependent variation is common in natural plant populations, implicating the chaperone as an important player in shaping phenotype and evolutionary trajectories (Sangster et al. 2008a,b). Together, these findings have prompted a longstanding debate about the importance of HSP90 in evolutionary processes and the magnitude of its effect (Meiklejohn and Hartl 2002;Bergman and Siegal 2003;Rando and Verstrepen 2007).It is well-established that HSP90 recognizes metastable proteins and facilitates their folding and stab...

Heat shock protein 90 acts in brassinosteroid signaling through interaction with BES1/BZR1 transcription factor

“…Recently, Samakovli et al (2014) reported that HSP90 interacts with a BR signaling component, BIN2 kinase, to modulate its nuclear retention. Independently of their study, HSP90 was also found to bind to BES1 (Lachowiec et al, 2013;Shigeta et al, 2014). These findings suggest the involvement and importance of HSP90 activity in BR signaling.…”

Survival and innovation: The role of mutational robustness in evolution

“…Accordingly, duplicated genes in yeast in which one of the gene copies, but not its paralog, is a client of Hsp90 shows faster evolution at the Hsp90 client copy than its non-client paralog [43]. Moreover, one of the two paralogs of a transcription factor in the brassinosteroid pathway in the plant Arabidopsis thaliana that requires Hsp90 for folding shows more relaxed constraints than its non-client paralog [43]. Since duplicates are considered identical or nearly so at their birth, such results are not artifacts caused by the differential protein stabilities.…”

A Recently Evolved Isoform of the Transcription Factor BES1 Promotes Brassinosteroid Signaling and Development in Arabidopsis thaliana

“…However, BES1 has five predicted gene models encoding two possible proteins based on The Arabidopsis Information Resource (Lamesch et al, 2012;Lachowiec et al, 2013). Sequence analysis indicated that At1G19350.3 arises from an alternative transcription initiation (ATI) at another upstream transcription start site (TSS) and an alternative splicing (AS), thus encoding a longer protein with additional 22 amino acid residues at the N terminus ( Figure 1A).…”

“…To avoid the deleterious effects of mutation, gene duplication events occur to allow one copy of a gene to maintain its function, while another copy may diverge to acquire new functions (Sayou et al, 2014). BES1 and BZR1 belong to a small gene family encoding plant-specific transcription factors, and they may have originated from a common ancestor and then diverged (Yin et al, 2005;Lachowiec et al, 2013). A previous examination of the dN/dS ratio, which is used to infer the direction and magnitude of the effect of natural selection on protein-coding genes, revealed that compared with BZR1, BES1 has been undergoing relaxed purifying selection, suggesting that BES1 may have a more rapid evolution rate.…”

“…A previous examination of the dN/dS ratio, which is used to infer the direction and magnitude of the effect of natural selection on protein-coding genes, revealed that compared with BZR1, BES1 has been undergoing relaxed purifying selection, suggesting that BES1 may have a more rapid evolution rate. Furthermore, the molecular chaperone heat shock protein 90 acts as a capacitor to tolerate changes in its client BES1, allowing BES1 to evolve rapidly (Lachowiec et al, 2013). To evaluate the evolutionary novelty of BES1-L, we constructed a phylogenetic tree of BES1 proteins from multiple flowering plant species.…”