Cytochromes c (Cyt c) are ubiquitous heme-containing proteins, mainly involved in electron transfer processes, whose structure and functions have been and still are intensely studied. Surprisingly, our understanding of the molecular mechanism whereby the heme group is covalently attached to the apoprotein (apoCyt) in the cell is still largely unknown. This posttranslational process, known as Cyt c biogenesis or Cyt c maturation, ensures the stereospecific formation of the thioether bonds between the heme vinyl groups and the cysteine thiols of the apoCyt heme binding motif. To accomplish this task, prokaryotic and eukaryotic cells have evolved distinctive protein machineries composed of different proteins. In this review, the structural and functional properties of the main maturation apparatuses found in gram-negative and gram-positive bacteria and in the mitochondria of eukaryotic cells will be presented, dissecting the Cyt c maturation process into three functional steps: (i) heme translocation and delivery, (ii) apoCyt thioreductive pathway, and (iii) apoCyt chaperoning and heme ligation. Moreover, current hypotheses and open questions about the molecular mechanisms of each of the three steps will be discussed, with special attention to System I, the maturation apparatus found in gram-negative bacteria. 1. Introduction Cytochromes c (Cyts c) are ubiquitous heme-containing proteins involved in a variety of critical processes of cellular metabolism; since their discovery by Keilin in the early 1920s, they have been the focus of multidisciplinary scientific interests and nowadays are considered textbook proteins in biochemistry courses. However, many aspects of c-type cytochromes are still to be unveiled, from the control and fine-tuning of electron transfer reactions and heme reactivity [1–3] to the description of Cyt c folding pathways and stability [4–6]. The presence of the covalently bound heme prosthetic group dictates the functions of Cyts c, which are associated mainly with electron transfer processes in aerobic and anaerobic respiration and in photosynthesis [7, 8]; however, it is now clear that Cyts c play important roles also in other cellular processes such as H2O2 scavenging, cytochrome c oxidase assembly [9], lipid signaling [10], or apoptotic processes in the eukaryotic cells [11, 12]. This review deals with a complex and still largely unknown process, whereby the heme is covalently and stereospecifically attached to the apoprotein (apoCyt) in the cell; this posttranslational process is known as Cyt c biogenesis or Cyt c maturation. Over
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