Navigating Among Known Structures in Protein Space

Narunsky, Aya; Ben‐Tal, Nir; Kolodny, Rachel

doi:10.1007/978-1-4939-8736-8_12

Cited by 2 publications

(2 citation statements)

References 86 publications

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“…The functioning of proteins is assured by the presence of functionally important regions and modules, which can be organized at different structural levels, from primary through secondary to tertiary, three-dimensional (3D) structures [ 1 ]. These modules include independently folded 3D domains, secondary structure elements (SSEs), and short linear motifs (SLiMs), which provide multimodular and multifunctional features of many proteins [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

Short Linear Motifs Orchestrate Functioning of Human Proteins during Embryonic Development, Redox Regulation, and Cancer

et al. 2022

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Short linear motifs (SLiMs) are evolutionarily conserved functional modules of proteins that represent amino acid stretches composed of 3 to 10 residues. The biological activities of two short peptide segments of human alpha-fetoprotein (AFP), a major embryo-specific and cancer-related protein, have been confirmed experimentally. This is a heptapeptide segment LDSYQCT in domain I designated as AFP14–20 and a nonapeptide segment EMTPVNPGV in domain III designated as GIP-9. In our work, we searched the UniprotKB database for human proteins that contain SLiMs with sequence similarity to the both segments of human AFP and undertook gene ontology (GO)-based functional categorization of retrieved proteins. Gene set enrichment analysis included GO terms for biological process, molecular function, metabolic pathway, KEGG pathway, and protein–protein interaction (PPI) categories. We identified the SLiMs of interest in a variety of non-homologous proteins involved in multiple cellular processes underlying embryonic development, cancer progression, and, unexpectedly, the regulation of redox homeostasis. These included transcription factors, cell adhesion proteins, ubiquitin-activating and conjugating enzymes, cell signaling proteins, and oxidoreductase enzymes. They function by regulating cell proliferation and differentiation, cell cycle, DNA replication/repair/recombination, metabolism, immune/inflammatory response, and apoptosis. In addition to the retrieved genes, new interacting genes were identified. Our data support the hypothesis that conserved SLiMs are incorporated into non-homologous proteins to serve as functional blocks for their orchestrated functioning.

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Section: Introductionmentioning

confidence: 99%

Short Linear Motifs Orchestrate Functioning of Human Proteins during Embryonic Development, Redox Regulation, and Cancer

et al. 2022

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“…Because evolution is driven by progressive mutations and selection pressure, the sequences of the native proteins are not evenly distributed throughout the sequence space. Instead, they form a family of proteins with similar amino acid sequences, structures, and functions [ 4 ]. Exploring the large sequence space outside the evolutionary path requires the de novo design of proteins [ 5 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

A De Novo Designed Esterase with p-Nitrophenyl Acetate Hydrolysis Activity

Zhang

et al. 2020

Molecules

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Esterases are a large family of enzymes with wide applications in the industry. However, all esterases originated from natural sources, limiting their use in harsh environments or newly- emerged reactions. In this study, we designed a new esterase to develop a new protocol to satisfy the needs for better biocatalysts. The ideal spatial conformation of the serine catalytic triad and the oxygen anion hole at the substrate-binding site was constructed by quantum mechanical calculation. The catalytic triad and oxygen anion holes were then embedded in the protein scaffold using the new enzyme protocol in Rosetta 3. The design results were subsequently evaluated, and optimized designs were used for expression and purification. The designed esterase had significant lytic activities towards p-nitrophenyl acetate, which was confirmed by point mutations. Thus, this study developed a new protocol to obtain novel enzymes that may be useful in unforgiving environments or novel reactions.

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Navigating Among Known Structures in Protein Space

Cited by 2 publications

References 86 publications

Short Linear Motifs Orchestrate Functioning of Human Proteins during Embryonic Development, Redox Regulation, and Cancer

Short Linear Motifs Orchestrate Functioning of Human Proteins during Embryonic Development, Redox Regulation, and Cancer

A De Novo Designed Esterase with p-Nitrophenyl Acetate Hydrolysis Activity

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