From lifeless viral particles to complex multicellular organisms, membrane fusion is inarguably the important fundamental biological phenomena. Sitting at the heart of membrane fusion are protein mediators known as fusogens. Despite the extensive functional and structural characterization of these proteins in recent years, scientists are still grappling with the fundamental mechanisms underlying membrane fusion. From an evolutionary perspective, fusogens follow divergent evolutionary principles in that they are functionally independent and do not share any sequence identity; however, they possess structural similarity, raising the possibility that membrane fusion is mediated by essential motifs ubiquitous to all. In this review, we particularly emphasize structural characteristics of small-molecular-weight fusogens in the hope of uncovering the most fundamental aspects mediating membrane–membrane interactions. By identifying and elucidating fusion-dependent functional domains, this review paves the way for future research exploring novel fusogens in health and disease.
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