A structural atlas of death domain fold proteins reveals their versatile roles in biology and function

• 成果类型: Article
• 署名作者: Wu, Emily J.; Kandalkar, Ankita T.; Ehrmann, Julian F.; Tong, Alexander B.; Zhang, Jing; Cong, Qian; Wu, Hao
• 署名单位: Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Program in Cellular & Molecular Medicine (PCMM); Northeastern University; University of California System; University of California Berkeley; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11770
• DOI: 10.1073/pnas.2426986122
• 发表日期: 2025-02-20
• 关键词: cryo-em structure; crystal-structure; nmr structure; pyrin domain; caspase-9 activation; assembly mechanism; signal-activation; cd95 fas/apo-1; cell-death; rig-i

摘要

Death domain fold (DDF) superfamily proteins are critically important players in pathways of cell death and inflammation. DDFs are often essential scaffolding domains in receptors, adaptors, or effectors of these pathways by mediating homoand hetero- oligomerization including helical filament assembly. At the downstream ends of these pathways, effector oligomerization by DDFs brings the enzyme domains into proximity for their dimerization and activation. Hundreds of structures of these domains have been solved. However, a comprehensive understanding of DDFs is lacking. In this article, we report the curation of a DDF structural atlas as a public website (deathdomain.org) and deduce the common and distinct principles of or PYD). We further annotate DDFs genome- wide based on AlphaFold- predicted models and protein sequences. These studies reveal mechanistic rules for this widely distributed domain superfamily.