Date of Presentation
5-5-2022 12:00 AM
College
School of Osteopathic Medicine
Poster Abstract
For normal cell function, exogenous signals must be correctly interpreted, and the proper response executed. The mitochondria are key regulatory nodes of cellular fate. For example, mitochondria undergo fission and fusion cycles depending on the energetic needs of the cell. Additionally, regulated cell death pathways also function at the mitochondria. Cyclin C is a transcriptional regulator of stress response and growth control genes. Following stress, a portion of cyclin C translocates to the cytoplasm, where it interacts with both the mitochondrial fission and apoptotic machinery. Based on these findings, we hypothesize that Cyclin C represents a key mediator linking transcription to mitochondrial fission and intrinsic regulated cell death (iRCD). Cyclin C has two conserved cyclin box domains each composed of five alpha-helices, termed CB1 and CB2, which mediate protein-protein interactions with regards to transcriptional regulation (Cdk8) and mitochondrial fission (Drp1), respectively. Pull down studies show that both pro-apoptotic protein Bax and fission machinery protein Drp1 interact directly with cyclin C. Cyclin C interaction is required for Bax activation and efficient iRCD; however, Drp1 is required for this interaction to occur, suggesting a role for the interaction of all three proteins. Docking simulations show cyclin C and Bax interact directly through multiple sites within amino acids 160-170 of cyclin C. Inspection of this region shows a homologous BH2 sequence, similar to that of Bcl-2 protein family members. Prior work has demonstrated that while this sequence is required for Bax binding, it is not required for binding Drp1. To further support this, preliminary modeling data suggests Drp1 interaction is mediated through the latter half of CB2, which is downstream of this sequence. Taken together, these results suggest a model that cyclin C possesses three distinct interaction domains, leading cyclin C to physically bridge the fission and apoptotic machinery and allowing the cell to properly coordinate mitochondrial dynamics with iRCD pathways.
Keywords
Cyclin C, Apoptosis, Mitochondrial Dynamics, Apoptosis Regulatory Proteins, bcl-2-Associated X Protein
Disciplines
Genetic Processes | Genetic Structures | Medical Molecular Biology | Medicine and Health Sciences
Document Type
Poster
Included in
Genetic Processes Commons, Genetic Structures Commons, Medical Molecular Biology Commons
Modeling the Role of Cyclin C in Connecting Stress-Induced Mitochondrial Fission to Apoptosis
For normal cell function, exogenous signals must be correctly interpreted, and the proper response executed. The mitochondria are key regulatory nodes of cellular fate. For example, mitochondria undergo fission and fusion cycles depending on the energetic needs of the cell. Additionally, regulated cell death pathways also function at the mitochondria. Cyclin C is a transcriptional regulator of stress response and growth control genes. Following stress, a portion of cyclin C translocates to the cytoplasm, where it interacts with both the mitochondrial fission and apoptotic machinery. Based on these findings, we hypothesize that Cyclin C represents a key mediator linking transcription to mitochondrial fission and intrinsic regulated cell death (iRCD). Cyclin C has two conserved cyclin box domains each composed of five alpha-helices, termed CB1 and CB2, which mediate protein-protein interactions with regards to transcriptional regulation (Cdk8) and mitochondrial fission (Drp1), respectively. Pull down studies show that both pro-apoptotic protein Bax and fission machinery protein Drp1 interact directly with cyclin C. Cyclin C interaction is required for Bax activation and efficient iRCD; however, Drp1 is required for this interaction to occur, suggesting a role for the interaction of all three proteins. Docking simulations show cyclin C and Bax interact directly through multiple sites within amino acids 160-170 of cyclin C. Inspection of this region shows a homologous BH2 sequence, similar to that of Bcl-2 protein family members. Prior work has demonstrated that while this sequence is required for Bax binding, it is not required for binding Drp1. To further support this, preliminary modeling data suggests Drp1 interaction is mediated through the latter half of CB2, which is downstream of this sequence. Taken together, these results suggest a model that cyclin C possesses three distinct interaction domains, leading cyclin C to physically bridge the fission and apoptotic machinery and allowing the cell to properly coordinate mitochondrial dynamics with iRCD pathways.