Evolution of intrinsic disorder in eukaryotic proteins

Ahrens, Joseph B.; Nunez-Castilla, Janelle; Siltberg-Liberles, Jessica

doi:10.1007/s00018-017-2559-0

Cited by 66 publications

(62 citation statements)

References 115 publications

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“…Linkers at all locations are on average more than twice as long in eukaryotes than in prokaryotes. Eukaryotic linkers are more disordered Eukaryotic proteins are more disordered than prokaryotic ones, see Figure 2b and c. In agreement with earlier studies [15,[41][42][43] 5% of the residues in prokaryotes are predicted to be disordered compared with 23% in eukaryotes. The increase in disorder is independent of the type of protein, but proteins that are specific to eukaryotes are more disordered than the ones that contain a shared domain.…”

Section: /30supporting

confidence: 90%

“…Further, the amount of intrinsic disorder is lower than expected by chance in both eukaryotes and prokaryotes [31]. Therefore it is possible that the lower selective pressure could explain why eukaryotes contain more disordered residues [15]. The basis of this argument is that the majority of the disordered residues are unfavorable, at least in prokaryotes, and therefore a selective pressure act against them.…”

Section: Discussionmentioning

confidence: 99%

“…It has been proposed that intrinsic disorder, as well as the other features separating eukaryotic and prokaryotic proteins, is a result of low selective pressure and small effective population size [15]. The authors argue that low selective pressure in eukaryotes causes the expansion of non-coding regions in eukaryotic genomes, as there is no strong purifying selection to keep it compact.…”

Section: Introductionmentioning

confidence: 99%

“…Intrinsically disordered proteins exist among many classes of proteins with different functions, but the difference between eukaryotic and prokaryotic proteins appears to be maintained. On average fewer than 10% of the residues in prokaryotes are disordered regions compared with more than 20% in eukaryotes [15]. Disordered regions are overrepresented in regulatory proteins [16], providing a possible explanation for why the need for such regions is increased in eukaryotes.It should, however, be remembered that the vast majority of studies of intrinsic disorder are based on predictions [17].…”

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Why do eukaryotic proteins contain more intrinsically disordered regions?

Basile

Elofsson

2018

Preprint

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Intrinsic disorder is much more abundant in eukaryotic than in prokaryotic proteins. However, the reason behind this is unclear. It has been proposed that the disordered regions are functionally important for regulation in eukaryotes, but it has also been proposed that the difference is a result of lower selective pressure in eukaryotes. Almost all studies intrinsic disorder is predicted from the amino acid sequence of a protein. Therefore, there should exist an underlying difference in the amino acid distributions between eukaryotic and prokaryotic proteins causing the predicted difference in intrinsic disorder. To obtain a better understanding of why eukaryotic proteins contain more intrinsically disordered regions we compare proteins from complete eukaryotic and prokaryotic proteomes.Here, we show that the difference in intrinsic disorder origin from differences in the linker regions. Eukaryotic proteins have more extended linker regions and, in particular, the eukaryotic linker regions are more disordered. The average eukaryotic protein is about 500 residues long; it contains 250 residues in linker regions, of which 80 are disordered. In comparison, prokaryotic proteins are about 350 residues long and only have 100-110 residues in linker regions, and less than 10 of these are intrinsically disordered.Further, we show that there is no systematic increase in the frequency of disorder-promoting residues in eukaryotic linker regions. Instead, the difference in frequency of only three amino acids seems to lie behind the difference. The most significant difference is that eukaryotic linkers contain about 9% serine, while prokaryotic linkers have roughly 6.5%. Eukaryotic linkers also contain about 2% more proline and 2-3% fewer isoleucine residues. The reason why primarily these amino acids vary in frequency is not apparent, but it cannot be excluded that the difference is serine is related to the increased need for regulation through phosphorylation and that the proline difference is related to increase of eukaryotic specific repeats.1/30 domains [11]. With a larger fraction of multi-domain proteins, it follows that eukaryotic proteins should have more linker regions -connecting the domains. Linker regions vary substantially in lengths and are often intrinsically disordered [12].The increased number of repeats appears to be a feature of multicellular organisms [8]. Repeat proteins are common in signaling and are associated with some cancers. These repeats have been proposed to provide the eukaryotes with an extra source of variability to compensate for low generation rates [13].The origin of the increase in intrinsically disordered regions in eukaryotic proteins is less well understood. Intrinsic disorder is frequent in all eukaryotic phyla, and even among viral proteins [14]. There is a spectrum of different types of disorder, spanning from increased flexibility to completely disordered proteins. Intrinsically disordered proteins exist among many classes of proteins with different functions, but the difference bet...

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Section: /30supporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Why do eukaryotic proteins contain more intrinsically disordered regions?

Basile

Elofsson

2018

Preprint

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“…Deletion of the acidic tract (D33-40) nearly abolished PCSK9-LDL binding while replacement of the hydrophobic residues with the Gly/Ser 41-46 linker reduced binding by >60%, suggestive of a functional overlap between these sequences (Figure 2A and B). As recently reported (28), secondary structure predictions using PSIPRED (31) showed an a-helical structure in this region with highest confidence for residues [38][39][40][41][42][43][44][45] (YEELVLAL) overlapping the acidic and hydrophobic segments (Figures 2C). Helical wheel modeling revealed characteristics of an amphipathic a-helix (AH) for these residues, with a relatively polar face and an opposing face consisting of aromatic (Tyr-38) and nonpolar amino acids (Leu-41, Val-42 and Leu-45), giving the helix a directional hydrophobic moment ( Figure 2D) (32).…”

supporting

confidence: 75%

A transient amphipathic helix in PCSK9’s prodomain facilitates low-density lipoprotein binding

Sarkar

Foo

Matyas

et al. 2019

Preprint

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Keywords: proprotein convertase subtilisin/kexin type 9 (PCSK9), low-density lipoprotein (LDL), cholesterol regulation, intrinsically disordered protein, conformational change, computer modeling SUMMARYProprotein convertase subtilisin/kexin type-9 (PCSK9) is a ligand of low-density lipoprotein receptor (LDLR) that promotes LDLR degradation in late endosomes/lysosomes. In human plasma, 30-40% of PCSK9 is bound to LDL particles; however, the physiological significance of this interaction remains unknown. LDL binding in vitro requires a disordered N-terminal region in PCSK9's prodomain. Here we report that peptides corresponding to a predicted amphipathic ahelix in the prodomain N-terminus adopted helical structure in a membrane-mimetic environment; this effect was greatly enhanced by an R46L substitution representing an atheroprotective PCSK9 loss-of-function mutation. A helix-disrupting proline substitution within the putative a-helical motif in full-length PCSK9 lowered LDL binding affinity >5-fold. Modeling studies suggested the transient a-helix aligns multiple polar residues to interact with positivecharged residues in the C-terminal domain. Gain-of-function PCSK9 mutations associated with familial hypercholesterolemia (FH) and clustered at the predicted interdomain interface (R469W, R496W, F515L) inhibited LDL binding, which was abolished for the R496W variant. These studies inform on allosteric conformational changes in PCSK9 required for high-affinity binding to LDL particles. Moreover, we report the initial identification of FH-associated mutations that diminish the ability of PCSK9 to bind LDL, supporting that LDL association in the circulation inhibits PCSK9 activity. PCSK9 mutations in hypercholesterolemia

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Mechanosensitive ion channels MSL8, MSL9, and MSL10 have environmentally sensitive intrinsically disordered regions with distinct biophysical characteristics in vitro

et al. 2023

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Intrinsically disordered protein regions (IDRs) are highly dynamic sequences that rapidly sample a collection of conformations over time. In the past several decades, IDRs have emerged as a major component of many proteomes, comprising ~30% of all eukaryotic protein sequences. Proteins with IDRs function in a wide range of biological pathways and are notably enriched in signaling cascades that respond to environmental stresses. Here, we identify and characterize intrinsic disorder in the soluble cytoplasmic N‐terminal domains of MSL8, MSL9, and MSL10, three members of the MscS‐like (MSL) family of mechanosensitive ion channels. In plants, MSL channels are proposed to mediate cell and organelle osmotic homeostasis. Bioinformatic tools unanimously predicted that the cytosolic N‐termini of MSL channels are intrinsically disordered. We examined the N‐terminus of MSL10 (MSL10N) as an exemplar of these IDRs and circular dichroism spectroscopy confirms its disorder. MSL10N adopted a predominately helical structure when exposed to the helix‐inducing compound trifluoroethanol (TFE). Furthermore, in the presence of molecular crowding agents, MSL10N underwent structural changes and exhibited alterations to its homotypic interaction favorability. Lastly, interrogations of collective behavior via in vitro imaging of condensates indicated that MSL8N, MSL9N, and MSL10N have sharply differing propensities for self‐assembly into condensates, both inherently and in response to salt, temperature, and molecular crowding. Taken together, these data establish the N‐termini of MSL channels as intrinsically disordered regions with distinct biophysical properties and the potential to respond uniquely to changes in their physiochemical environment.

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Evolution of intrinsic disorder in eukaryotic proteins

Cited by 66 publications

References 115 publications

Why do eukaryotic proteins contain more intrinsically disordered regions?

Why do eukaryotic proteins contain more intrinsically disordered regions?

A transient amphipathic helix in PCSK9’s prodomain facilitates low-density lipoprotein binding

Mechanosensitive ion channels MSL8, MSL9, and MSL10 have environmentally sensitive intrinsically disordered regions with distinct biophysical characteristics in vitro

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