Hsp90 as a capacitor for morphological evolution

Rutherford, Scott; Lindquist, Susan

doi:10.1038/24550

Cited by 2,060 publications

(1,872 citation statements)

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“…This link is increasingly evident through laboratory evolution studies [21][22][23][24][25][26] . For instance, recent experiments studied the evolvability of the enzyme cytochrome P450.…”

Section: Robustness Facilitates Evolutionary Innovationsmentioning

confidence: 99%

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Gene duplications, robustness and evolutionary innovations

Wagner

2008

BioEssays

113

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Gene duplications, robustness and evolutionary innovations Gene duplications, robustness and evolutionary innovations AbstractMutational robustness facilitates evolutionary innovations. Gene duplications are unique kinds of mutations, in that they generally increase such robustness. The frequent association of gene duplications in regulatory networks with evolutionary innovation is thus a special case of a general mechanism linking innovation to robustness. The potential power of this mechanism to promote evolutionary innovations on large time scales is illustrated here with several examples. These include the role of gene duplications in the vertebrate radiation, flowering plant evolution and heart development, which encompass some of the most striking innovations in the evolution of life. Gene duplications, robustness, and evolutionary innovationsAndreas Wagner AbstractMutational robustness facilitates evolutionary innovations in biological systems. Gene duplications are unique kinds of mutations, in that they generally increase such robustness. The frequent association of gene duplications in regulatory networks with evolutionary innovation thus exemplifies a general mechanism linking innovation to robustness. I illustrate the potential power of this mechanism on large time scales with the role of gene duplications in the vertebrate radiation, flowering plant evolution, and heart development, which encompass some of the most striking innovations in the evolution of life. Mutational robustnessMutational robustness is a biological's system ability to withstand mutations. Such robustness exists on multiple levels of biological organization. A case in point are random mutagenesis experiments of various proteins. They suggest that only a small fraction of mutations affect protein function adversely. For instance, a study of the bacteriophage T4 lysozyme generated more than 2000 random amino acid changes in the protein. Only 16% of them affected lysozyme function 1 . Other examples come from regulatory gene networks, such as the molecular network specifying fruit fly segments. Such networks may tolerate much quantitative variation in interactions among network genes 2-5 . Examples at the highest level of organization include macroscopic traits. Even substantial genetic variation -ultimately caused by mutations -may leave such traits unchanged. Take the vulva of the nematode worms Caenorhabditis elegans and Pristionchus pacificus 6 . These organisms shared a common ancestor 200-300 million years ago. Their vulvae are very similar, yet the genetic and cellular networks producing them have diverged greatly. For example, whereas in C. elegans one specific cell -the anchor cell -induces vulva development, multiple gonadal cells are responsible for this induction in P. pacificus 7 . Similarly, the same key signaling molecules, such as Wnt, may play a positive role in the network for vulval induction in C. elegans, but a negative role in P. pacificus 8,9 . In sum, mutational robustness is everywhere, from proteins to or...

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“…This link is increasingly evident through laboratory evolution studies [21][22][23][24][25][26] . For instance, recent experiments studied the evolvability of the enzyme cytochrome P450.…”

Section: Robustness Facilitates Evolutionary Innovationsmentioning

confidence: 99%

“…One line of such work, beginning in the 1950s, focuses on morphological traits that normally show very little variation in wild populations 22,[27][28][29] . Through specific mutations, drug treatment, or environmental stress, such variation can be induced in a population.…”

Section: Robustness Facilitates Evolutionary Innovationsmentioning

confidence: 99%

Gene duplications, robustness and evolutionary innovations

Wagner

2008

BioEssays

113

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“…Hsp90 maintains mutant proteins in their functional state and hence silences the preexisting mutations in the genetic background. However, during stress, the Hsp90 reservoir is depleted which allows the emergence of hidden phenotypes from the mutant proteins that can be tolerated by cells, leading to genetic evolution Queitsch et al, 2002;Rutherford and Lindquist, 1998).…”

Section: Ii41122 the Hsp90 Chaperone Systemmentioning

confidence: 99%

Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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“…These altered morphologies were the result of an increased expression of cryptic genetic variations. With even lower levels of Hsp90 expression, more and more genetic variations became expressed (Rutherford & Lindquist, 1998). In nature, transient changes in the expression level of Hsp90 would allow for the selection of new phenotypic traits assisting in the evolution of the organism.…”

Section: Introductionmentioning

confidence: 99%

Conformational dynamics of the molecular chaperone Hsp90

Krukenberg

Street

Lavery

et al. 2011

Quart. Rev. Biophys.

271

262

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The molecular chaperone Hsp90 is an essential eukaryotic protein that makes up 1-2% of all cytosolic proteins. Hsp90 is vital for the maturation and maintenance of a wide variety of substrate proteins largely involved in signaling and regulatory processes. Many of these substrates have also been implicated in cancer and other diseases making Hsp90 an attractive target for therapeutics. Hsp90 is a highly dynamic and flexible molecule that can adapt its conformation to the wide variety of substrate proteins with which it acts. Large conformational rearrangements are also required for the activation of these client proteins. One driving force for these rearrangements is the intrinsic ATPase activity of Hsp90, as seen with other chaperones. However, unlike other chaperones, studies have shown that the ATPase cycle of Hsp90 is not conformationally deterministic. That is, rather than dictating the conformational state, ATP binding and hydrolysis shifts the equilibrium between a pre-existing set of conformational states in an organismdependent manner. In vivo Hsp90 functions as part of larger heterocomplexes. The binding partners of Hsp90, co-chaperones, assist in the recruitment and activation of substrates, and many co-chaperones further regulate the conformational dynamics of Hsp90 by shifting the conformational equilibrium towards a particular state. Studies have also suggested alternative mechanisms for the regulation of Hsp90's conformation. In this review, we discuss the structural and biochemical studies leading to our current understanding of the conformational dynamics of Hsp90 and the role that nucleotide, co-chaperones, post-translational modification and clients play in regulating Hsp90's conformation. We also discuss the effects of current Hsp90 inhibitors on conformation and the potential for developing small molecules that inhibit Hsp90 by disrupting the conformational dynamics.

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Hsp90 as a capacitor for morphological evolution

Cited by 2,060 publications

References 31 publications

Gene duplications, robustness and evolutionary innovations

Gene duplications, robustness and evolutionary innovations

Firefly luciferase mutants as sensors of proteome stress

Conformational dynamics of the molecular chaperone Hsp90

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