Protein Structure: Unusual Covalent Bonds

Abstract

Proteins are linear polypeptides made out of a small set of amino acids. The chemical diversity of the building blocks is limited, but a protein's covalent structure can be amended in vivo so that unusual linkages are introduced and new functionalities are conveyed. These covalent modifications may occur during translation or after the protein is fully synthesised; they may be spontaneous or enzymatic and transient or long lived. They are generally consequential to cellular function and integrity of the organism. The broad array of modification includes common and frequent substitutions such as phosphorylation and rarer alterations such as formylglycine formation. A survey of long‐lived modifications is presented from a physicochemical perspective with attention to biological relevance. Key Concepts: Covalent bonds other than found in the standard set of amino acids expand the chemical properties of proteins. Unusual bonds are found in protein‐derived prosthetic groups. Unusual covalent bonds play functional roles. Some unusual covalent bonds are irreversibly formed and are markers of aging. Many unusual bonds are reversibly formed and participate in regulatory mechanisms. Unusual bonds are often difficult to detect and identify, especially in vivo . Technological advances have improved the ability to detect modifications in entire proteomes.

Facile Heme Vinyl Posttranslational Modification in a Hemoglobin

“…Cysteine can react with the heme via reductive and oxidative mechanisms 13 and has additional options of deprotonation, methylation, phosphorylation, disulfide bridging (redox sensing), nitrosylation, and numerous other oxidative modifications. 46 This high reactivity allows multiple modes of regulation, some of which are critical in cytochrome c maturation. 13 In contrast, the opportunities for regulation of histidine−vinyl chemistry are more limited, principally to the iron redox state, pH, and histidine PTMs such as phosphorylation and methylation.…”

“…In natural proteins, the preference for cysteine–heme attachment is likely to stem not only from the properties of the product but also from the versatility of the thiol group. Cysteine can react with the heme via reductive and oxidative mechanisms and has additional options of deprotonation, methylation, phosphorylation, disulfide bridging (redox sensing), nitrosylation, and numerous other oxidative modifications . This high reactivity allows multiple modes of regulation, some of which are critical in cytochrome c maturation .…”