Abundance of intrinsic disorder in SV-IV, a multifunctional androgen-dependent protein secreted from rat seminal vesicle

Silvia Vilasi,Raffaele Ragone

doi:10.1038/npre.2007.1394.1

Abstract

AbstractThe potent immunomodulatory, anti-inflammatory and procoagulant properties of theprotein no. 4 secreted from the rat seminal vesicle epithelium (SV-IV) have beenpreviously found to be modulated by a supramolecular monomer-trimer equilibrium.More structural details that integrate experimental data into a predictive frameworkhave recently been reported. Unfortunately, homology modelling and fold-recognitionstrategies were not successful in creating a theoretical model of the structuralorganization of SV-IV. It was inferred that the global structure of SV-IV is not similarto any protein of known three-dimensional structure. Reversing the classical approachto the sequence-structure-function paradigm, in this paper we report on novelinformation obtained by comparing physicochemical parameters of SV-IV with twodatasets made of intrinsically unfolded and ideally globular proteins. In addition, wehave analysed the SV-IV sequence by several publicly available disorder-orientedpredictors. Overall, disorder predictions and a re-examination of existing experimentaldata strongly suggest that SV-IV needs large plasticity to efficiently interact with thedifferent targets that characterize its multifaceted biological function and should betherefore better classified as an intrinsically disordered protein.

Highlights

The view that a protein must fold into the right shape, as encoded in the amino acid sequence, before it can go to function has been deeply rooted in protein science, even before the 3D structure of a protein was first solved
Reversing the classical approach to the sequence-structure-function paradigm, in this paper we report on novel information obtained by comparing physicochemical parameters of SV-IV with two datasets made of intrinsically unfolded and ideally globular proteins
The structural information we have re-examined seems sufficient to raise the doubt that intrinsic disorder is abundant in SV-IV

Summary

Introduction

The view that a protein must fold into the right shape, as encoded in the amino acid sequence, before it can go to function has been deeply rooted in protein science, even before the 3D structure of a protein was first solved. For some proteins, especially those involved in signalling and regulation [1], the unstructured state has been suggested to be essential for basic cellular functions and recognized as a separate functional and structural category [2, 3] These are proteins or domains that, in their native state, are either completely disordered or contain large disordered regions, and do not fit the standard sequence-structurefunction paradigm, because intrinsic disorder, whether local or extended to the entire protein length, is crucially important for their function. On noting that homology modelling and fold-recognition strategies were not able to provide detailed structural information, they concluded that SV-IV assumes a global structure that is not similar to any protein of known 3D structure [22] Such an occurrence suggests that SV-IV could violate the standard sequence-structure-function paradigm, but the authors did not investigate this possibility. When dealing with proteins of uncertain 3D structure, it would be more correct and less time-expensive to look for disorder before trying modelling procedures

Methods

Results

Conclusion