9k8t | pdb_00009k8t
Cryo-EM structure of HE30 polymorph 2
Structural highlights
FunctionNINJ1_HUMAN Effector of necroptotic and pyroptotic programmed cell death that mediates plasma membrane rupture (cytolysis) (PubMed:33472215, PubMed:36468682, PubMed:37196676, PubMed:37198476). Acts downstream of Gasdermin (GSDMA, GSDMB, GSDMC, GSDMD, or GSDME) or MLKL during pyroptosis or necroptosis, respectively: oligomerizes in response to death stimuli and promotes plasma membrane rupture by introducing hydrophilic faces of 2 alpha helices into the hydrophobic membrane, leading to release intracellular molecules named damage-associated molecular patterns (DAMPs) that propagate the inflammatory response (PubMed:33472215, PubMed:36468682, PubMed:37196676, PubMed:37198476). Acts as a regulator of Toll-like receptor 4 (TLR4) signaling triggered by lipopolysaccharide (LPS) during systemic inflammation; directly binds LPS (PubMed:26677008). Involved in leukocyte migration during inflammation by promoting transendothelial migration of macrophages via homotypic binding (By similarity). Promotes the migration of monocytes across the brain endothelium to central nervous system inflammatory lesions (PubMed:22162058). Also acts as a homophilic transmembrane adhesion molecule involved in various processes such as axonal growth, cell chemotaxis and angiogenesis (PubMed:33028854, PubMed:8780658, PubMed:9261151). Promotes cell adhesion by mediating homophilic interactions via its extracellular N-terminal adhesion motif (N-NAM) (PubMed:33028854). Involved in the progression of the inflammatory stress by promoting cell-to-cell interactions between immune cells and endothelial cells (PubMed:22162058, PubMed:26677008, PubMed:32147432). Plays a role in nerve regeneration by promoting maturation of Schwann cells (PubMed:8780658, PubMed:9261151). Acts as a regulator of angiogenesis (PubMed:33028854). Promotes the formation of new vessels by mediating the interaction between capillary pericyte cells and endothelial cells (By similarity). Promotes osteoclasts development by enhancing the survival of prefusion osteoclasts (By similarity). Also involved in striated muscle growth and differentiation (By similarity).[UniProtKB:O70131][1] [2] [3] [4] [5] [6] [7] [8] [9] [10] Secreted form generated by cleavage, which has chemotactic activity (By similarity). Acts as an anti-inflammatory mediator by promoting monocyte recruitment, thereby ameliorating atherosclerosis (PubMed:32883094).[UniProtKB:O70131][11] Publication Abstract from PubMedAmyloid fibrils, defined by their cross-beta architecture, are central to both disease and function, yet the molecular principles governing their formation remain incompletely understood. Ninjurin-1 (NINJ1), a membrane protein essential for plasma membrane rupture (PMR) during cell death, contains an N-terminal amphipathic alpha-helix. Here, we investigate a key peptide fragment of this region (residues 40-69, HE30) and uncover its membrane-disruptive activity, self-assembly, and structural transitions. Monomeric HE30 reorganizes lipids to induce membrane thinning while undergoing an environmentally responsive alpha-helix-to-beta-sheet transition that drives amyloid fibril formation. Fibrils formed at physiological temperatures are predominantly nontwisted, but elevated temperatures induce left-handed twisted structures with variable pitches and lengths, and even result in high-order superhelical bundles. We further resolved the twisted fibril structures of HE30 by cryo-EM, revealing two distinct fibril polymorphs stabilized by both hydrophobic and electrostatic interactions. Consistently, salts inhibit HE30 fibrillation, emphasizing the role of electrostatic interactions in stabilizing fibrils. Moreover, acidic conditions ( approximately pH 4.4) promote fibril formation, whereas alkaline conditions lead to disassembly into alpha-helical monomers in a reversible manner. In situ AFM tracking reveals the asymmetric growth of fibrils, where one end elongates faster and the opposite end exhibits slower growth or complete inhibition. Functionally, HE30 fibrils are nontoxic and act as scaffolds for the temperature-controlled assembly of gold nanoparticle (AuNPs) superstructures. These findings not only advance our understanding of NINJ1-induced PMR but also provide a detailed structural basis for HE30 fibril formation via alpha-helix to beta-sheet transitions and underscore their potential as building blocks for fibril-based biomaterials. Amyloid Fibrillation of a Ninjurin-1-Derived alpha-Helical Peptide: Structural Insights into Conformational Transition.,Wang M, Xia W, Zhao D, Zhai Z, Chen R, Bai X, Zhang Z, Fan H, Zhang JP, Liu C, Jiao F ACS Nano. 2025 Oct 14;19(40):35977-35991. doi: 10.1021/acsnano.5c14731. Epub 2025 , Oct 2. PMID:41037056[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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