Insights into Programmed Cell Death through Structural Biology

(Strauss et al., 1999). Inappropriate apoptosis also contributes to several neurological disorders. In Alzheimer’s, Parkinson’s, and Huntington’s disease, specific Stephen W. Fesik* Abbott Laboratories Abbott Park, Illinois 60064 neurons prematurely commit suicide, which can lead to irreversible memory loss, uncontrolled muscular movements, and depression. Programmed cell death plays a critical role in controlling In the last few years, much has been learned about the number of cells in development and throughout an the signal transduction pathways of programmed cell organism’s life by the removal of cells at the appropriate death, providing us with insight into how programmed time. It is an important biological process for the eliminacell death works and how dysregulation of apoptosis tion of unwanted cells such as those with potentially contributes to disease. The overall process of proharmful genomic mutations, autoreactive lymphocytes, grammed cell death occurs in several stages. In the first or virally infected cells. Alterations of this normal prostep, the apoptotic pathway is triggered, which can be cess can result in the disruption of the delicate balance accomplished by a wide variety of stimuli, including DNA between cell proliferation and cell death and can lead damage, growth factor withdrawal, toxins, and radiation. to a variety of diseases (Thompson, 1995). For example, Once activated, the signal is transduced by a series of in many forms of cancer, key proapoptotic proteins are protein–protein interactions that involve a conserved set mutated or antiapoptotic proteins are upregulated, leadof signaling modules. In the next stage, cell death is ing to the accumulation of cells and the inability to executed by the activation of specific proteases called respond to harmful mutations, DNA damage, or chemocaspases that cleave multiple substrates, leading to therapeutic agents. Since effective chemotherapy dechanges characteristic of apoptotic cells such as DNA pends on the induction of programmed cell death, canfragmentation, chromatin condensation, cell shrinkage, cers with defects in the cell death signaling pathways and membrane blebbing. are particularly difficult to treat. Programmed cell death The signaling pathways of programmed cell death can is also important for eliminating autoreactive T cells after be divided into two components, involving either the an immune response. When this normal process is dismitochondria or death receptors (Figure 1) (Budihardjo rupted through mutations of the proteins that trigger et al., 1999). In the death receptor pathway, receptors apoptosis (e.g., Fas ligand or the Fas receptor), an autosuch as TNFR1, Fas, DR-3, DR-4, or DR-5 interact with immune lymphoproliferative syndrome (ALPS) can result, their cognate ligands. This binding event allows the with complications such as hypersplenism, autoimmune hemolytic anemia, thrombocytopenia, and neutropenia recruitment of downstream signaling partners, which