Diversity in the origins of proteostasis networks--a driver for protein function in evolution

Abstract

Although the sequence of a protein largely determines its function, proteins can adopt different folding states in response to changes in the environment, some of which may be deleterious to the organism. All organisms--Bacteria, Archaea and Eukarya--have evolved a protein homeostasis, or proteostasis, network comprising chaperones and folding factors, degradation components, signalling pathways and specialized compartmentalized modules that manage protein folding in response to environmental stimuli and variation. Surveying the origins of proteostasis networks reveals that they have co-evolved with the proteome to regulate the physiological state of the cell, reflecting the unique stresses that different cells or organisms experience, and that they have a key role in driving evolution by closely managing the link between the phenotype and the genotype.

Figure 1. Proteostasis operates as a cloud

a | Illustrated is the hierarchy of proteostasis biology components and the molecular signaling and trafficking pathways that direct the response of a cell or a species to the environment . The grey cloud icon highlights the local proteostasis network in a given cell type or species managing the fold. b | Illustrated is the impact of the quinary (5°) physiologic state (grey cloud) managed by proteostasis network on the generation the different secondary (2°, domain folded), ternary (intra-domain folded), and quaternary (multi-protein complex) structural states encoded by the primary polypeptide (1°) sequence encoded by the genome. The many different quinary state folding management environments generated by endomembrane compartments, including membrane trafficking compartments, mitochondria and chloroplasts among others, are illustrated by a blue oval cloud. c | Proteostasis serves as a folding buffer that surrounds every protein to manage the biological protein fold in evolution, and in health and disease. In the left hand panel, a protein (illustrated as black and green nodes in a protein interaction network) interacts with a local set of proteostasis network components (green cloud) to manage its normal function in a cell harboring a normal proteostasis network. In response to an inherited single nucleotide polymorphism or mutation and/or environmental stress (upper curved arrow), a protein misfolds (grey node) resulting in a disruption of binding of its normal partners (light green nodes) and new linkages to other proteins (pink nodes). Such misfolding cascades challenge proteostasis biology to fix the problem by changing its composition (pink cloud). Once fixed (lower arrow) (if fixable) the system returns to normal.

Figure 2. Diversity in origins of proteostasis

Shown is the evolution of HSPs among the extant three kingdoms of life- Bacteria, Archaea and Eukarya. Vertical arrows indicate increasing genome size and in number of genes expressed. The number of HSP40, HSP70 and HSP90 chaperones, of HSP60 chaperonin family subunits and of sHSPs and HSP100s found in each species are indicated. See Supplemental Table S1 and Figure S1 for further details and references.

Figure 2. Diversity in origins of proteostasis

Shown is the evolution of HSPs among the extant three kingdoms of life- Bacteria, Archaea and Eukarya. Vertical arrows indicate increasing genome size and in number of genes expressed. The number of HSP40, HSP70 and HSP90 chaperones, of HSP60 chaperonin family subunits and of sHSPs and HSP100s found in each species are indicated. See Supplemental Table S1 and Figure S1 for further details and references.

Figure 3. Role of proteostasis biology in evolvability

a | Proteostasis is normally optimized to support protein function (pink). However, it can also be limiting (fail to support folding) in response to metabolic, physiologic and environmental folding stress, and/or an inherited SNPs or mutations (orange). Alternatively, it can be bolstered (green) to support misfolding events in response to stress signaling pathways. b | A destabilizing mutation (red sphere) could not only fail to fold and lose function, but also challenge what was normally an ‘acceptable’ local folding environment to create one which has lost some aspect of its function in response to proteostasis stress (path 1 to orange)^, . A protein carrying such a destabilizing mutation could be degraded because it is not protected by proteostasis. Alternatively, a rapid change accommodated by proteostasis biology in response to a need for survival can occur through either acute and/or chronic changes in proteostasis network composition via signaling pathways (path 2 to green), thereby providing some level of protection to the cell and species. c | An inactive cryptic variant protected by proteostasis biology in a species becomes an active cryptic variant in response to a stress challenge (path 1 to orange). Such a variant could be incorporated into the genome in subsequent generations if the change in function provided an immediately more favorable survival outcome. Alternatively, the selective pressure for use of the active cryptic variant could be sustained through either genetic (green sphere)) and/or epigenetic mechanisms that could modify the proteostasis network^, , creating a new fold tolerance state (dotted paths to light maroon). Further evolution reflecting the new functional status of the cell would consolidate the proteostasis network function (path 3 to dark maroon). Thus, the proteostasis network strongly impacts the function of folding variants hidden in a population, and their short and long-term management by the proteostasis contributes to species evolability. Destabilized proteins are depicted as more transparent.