Abstract
Viral capsid proteins assemble into large, symmetrical architectures that are not found in complexes formed by their cellular counterparts. Given the prevalence of the signature jelly-roll topology in viral capsid proteins, we are interested in whether these functionally unique capsid proteins are also structurally unique in terms of folds. To explore this question, we applied a structure-alignment based clustering of all protein chains in VIPERdb filtered at 40% sequence identity to identify distinct capsid folds, and compared the cluster medoids with a non-redundant subset of protein domains in the SCOP database, not including the viral capsid entries. This comparison, using Template Modeling (TM)-score, identified 2078 structural “relatives” of capsid proteins from the non-capsid set, covering altogether 210 folds following the definition in SCOP. The statistical significance of the 210 folds shared by two sets of the same sizes, estimated from 10,000 permutation tests, is less than 0.0001, which is an upper bound on the p-value. We thus conclude that viral capsid proteins are segregated in structural fold space. Our result provides novel insight on how structural folds of capsid proteins, as opposed to their surface chemistry, might be constrained during evolution by requirement of the assembled cage-like architecture. Also importantly, our work highlights a guiding principle for virus-based nanoplatform design in a wide range of biomedical applications and materials science.
Highlights
Viral capsid proteins protect the viral genome by forming a closed protein shell around it
While T = 1 viruses can place each protein in an identical environment, other viruses having multiple proteins per icosahedral asymmetric unit (IAU) achieve the symmetry by following the ‘quasiequivalence’ principle proposed by Caspar and Klug [3]
We present, to the best of our knowledge, the first attempt to examine whether the structural folds of viral capsid proteins set them apart from generic proteins, and with how much statistical significance
Summary
Viral capsid proteins protect the viral genome by forming a closed protein shell around it. We make a distinction between protein cages in viral capsid shells that have sizes ranging from about 10 nm to about 90 nm in radius (Figure 1A), and other oligomeric containers of a much smaller scale, such as ferritins and chaperones. In the simplest form, 60 identical copies of an icosahedral asymmetric unit (IAU) are assembled with 5:3:2 symmetry, by positioning three IAUSs on each of the 20 triangular faces of the icosahedron [2]. While T = 1 viruses can place each protein in an identical environment, other viruses having multiple proteins per IAU achieve the symmetry by following the ‘quasiequivalence’ principle proposed by Caspar and Klug [3]. Worth noting is that large viruses, such as double-stranded RNA (dsRNA) viruses, deviate from this principle, while preserving a rigid icosahedral symmetry [2]
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