Disorder and cysteines in proteins: A design for orchestration of conformational see-saw and modulatory functions

Bhopatkar, Anukool A.; Uversky, Vladimir N.; Rangachari, Vijayaraghavan

doi:10.1016/bs.pmbts.2020.06.001

Cited by 30 publications

(28 citation statements)

References 169 publications

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“…In spite of the overall similarity in the composition profile of fungal and bacterial dCTRs of the AA10 family, more subtle differences can be discerned: fungal dCTRs are in fact enriched in Cys, Tyr, Met, Arg, Gln, Ser, Asn, Lys, while bacterial dCTRs display more Ala, Gly, Pro, Val, Leu, Asp, Glu, in agreement with the overall composition of low complexity regions in bacteria [59]. Remarkably, dCTRs from the AA11 and AA15 families are particularly enriched in cysteine residues, which could drastically affect the functionality and conformation of these regions [60]. Furthermore, as few as five amino acids (Ser, Thr, Pro, Gly and Ala) constitute on average as much as half of the composition of dCTRs (Figure S4).…”

Section: Most Dctrs Are Enriched In Serine and Threonine Residuesmentioning

confidence: 67%

Bioinformatic Analysis of Lytic Polysaccharide Monooxygenases Reveals the Pan-Families Occurrence of Intrinsically Disordered C-Terminal Extensions

et al. 2021

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Lytic polysaccharide monooxygenases (LPMOs) are monocopper enzymes secreted by many organisms and viruses. LPMOs catalyze the oxidative cleavage of different types of polysaccharides and are today divided into eight families (AA9–11, AA13–17) within the Auxiliary Activity enzyme class of the CAZy database. LPMOs minimal architecture encompasses a catalytic domain, to which can be appended a carbohydrate-binding module. Intriguingly, we observed that some LPMO sequences also display a C-terminal extension of varying length not associated with any known function or fold. Here, we analyzed 27,060 sequences from different LPMO families and show that 60% have a C-terminal extension predicted to be intrinsically disordered. Our analysis shows that these disordered C-terminal regions (dCTRs) are widespread in all LPMO families (except AA13) and differ in terms of sequence length and amino-acid composition. Noteworthily, these dCTRs have so far only been observed in LPMOs. LPMO-dCTRs share a common polyampholytic nature and an enrichment in serine and threonine residues, suggesting that they undergo post-translational modifications. Interestingly, dCTRs from AA11 and AA15 are enriched in redox-sensitive, conditionally disordered regions. The widespread occurrence of dCTRs in LPMOs from evolutionarily very divergent organisms, hints at a possible functional role and opens new prospects in the field of LPMOs.

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Section: Most Dctrs Are Enriched In Serine and Threonine Residuesmentioning

confidence: 67%

Bioinformatic Analysis of Lytic Polysaccharide Monooxygenases Reveals the Pan-Families Occurrence of Intrinsically Disordered C-Terminal Extensions

et al. 2021

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“…Cysteine residues contribute to the stability of the tertiary structure 56 of the protein through the formation of disulfide bonds and its sensitivity to redox stress, donating thiol groups 96 to interact with reactive oxygen species 61,62,97 . The aromatic amino acids Phe, Tyr, and Trp also increase the internal ordering of proteins 56,57 . It should be noted that this trend is not typical for all chaperone families.…”

Section: Discussionmentioning

confidence: 99%

“…To determine the degree of influence of amino acid residues on the internal ordering of a protein structure, the special scale of residues is used "Trp, Phe, Tyr, Ile, Met, Leu, Val, Asn, Cys, Thr, Ala, Gly, Arg, Asp, His, Gln, Lys, Ser, Glu, Pro". 56,57 According to this rating, internally ordered proteins must contain a sufficient amount of aromatic residues (Phe, Tyr, Trp), aliphatic residues (Ile, Leu, Val, and Ala), as well as Cys and Thr.…”

Section: Amino Acid Composition Of Hsp60mentioning

confidence: 99%

In‐depth analysis of amino acid and nucleotide sequences of Hsp60: How conserved is this protein?

et al. 2022

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Chaperonin Hsp60, as a protein found in all organisms, is of great interest in medicine, since it is present in many tissues and can be used both as a drug and as an object of targeted therapy. Hence, Hsp60 deserves a fundamental comparative analysis to assess its evolutionary characteristics. It was found that the percent identity of Hsp60 amino acid sequences both within and between phyla was not high enough to identify Hsp60s as highly conserved proteins. However, their ATP binding sites are largely conserved. The amino acid composition of Hsp60s remained relatively constant. At the same time, the analysis of the nucleotide sequences showed that GC content in the Hsp60 genes was comparable to or greater than the genomic values, which may indicate a high resistance to mutations due to tight control of the nucleotide composition by DNA repair systems. Natural selection plays a dominant role in the evolution of Hsp60 genes. The degree of mutational pressure affecting the Hsp60 genes is quite low, and its direction does not depend on taxonomy. Interestingly, for the Hsp60 genes from Chordata, Arthropoda, and Proteobacteria the exact direction of mutational pressure could not be determined. However, upon further division into classes, it was found that the direction of the mutational pressure for Hsp60 genes from Fish differs from that for other chordates. The direction of the mutational pressure affects the synonymous codon usage bias. The number of high and low represented codons increases with increasing GC content, which can improve codon usage. Special server has been created for bioinformatics analysis of Hsp60: http://oka.protres.ru:4202/.

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“…It is also noteworthy that the presence of redox‐sensitive proteins increases with increasing organism complexity 25 . Furthermore in eukaryotes, there exists a linear correlation between proteins containing disordered sequences and degree of cysteines within them 28 . Among the proteins containing more than 20% cysteines, GRNs show similarities to metallothioneins (MTs), which are ~60 amino acid long proteins consisting of 20 cysteines (33%) 29 .…”

Section: Introductionmentioning

confidence: 99%

Are granulins copper sequestering proteins?

Bhopatkar

Rangachari

2020

Proteins

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Granulins (GRN 1‐7) are short (~6 kDa), cysteine‐rich proteins that are generated upon the proteolytic processing of progranulin (PGRN). These peptides, along with their precursor, have been implicated in multiple pathophysiological roles, especially in neurodegenerative diseases. Previously we showed that GRN‐3 and GRN‐5 are fully disordered in the reduced form implicating redox sensitive attributes to the proteins. Redox‐based modulations are often carried out by metalloproteins in mitigating oxidative stress and maintaining metal‐homeostasis within cells. To probe whether GRNs play a role in metal sequestration, we tested the metal binding propensity of the reduced forms of GRNs −3 and − 5 under neutral and acidic pH mimicking cytosolic and lysosomal conditions, respectively. We found, at neutral pH, both GRNs selectively bind Cu and no other divalent metal cations, with a greater specificity for Cu(I). Binding of Cu did not result in a disorder‐to‐order structural transition but partly triggered the multimerization of GRNs via uncoordinated cystines at both pH conditions. Overall, the results indicate that GRNs −3 and − 5 have surprisingly strong affinity for Cu in the pM range, comparable to other known copper sequestering proteins. The results also hint at a potential of GRNs to reduce Cu(II) to Cu(I), a process that has significance in mitigating Cu‐induced ROS cytotoxicity in cells. Together, this report uncovers metal‐coordinating property of GRNs for the first time, which may have profound significance in their structure and pathophysiological functions.

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Disorder and cysteines in proteins: A design for orchestration of conformational see-saw and modulatory functions

Cited by 30 publications

References 169 publications

Bioinformatic Analysis of Lytic Polysaccharide Monooxygenases Reveals the Pan-Families Occurrence of Intrinsically Disordered C-Terminal Extensions

Bioinformatic Analysis of Lytic Polysaccharide Monooxygenases Reveals the Pan-Families Occurrence of Intrinsically Disordered C-Terminal Extensions

In‐depth analysis of amino acid and nucleotide sequences of Hsp60: How conserved is this protein?

Are granulins copper sequestering proteins?

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