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Abstract
BackgroundProteins with low sequence identity but almost identical tertiary structure and function have been valuable to uncover the relationship between sequence, tertiary structure, folding mechanism and functions. Two homologous chemokines, CCL11 and CCL24, with low sequence identity but similar tertiary structure and function, provide an excellent model system for respective studies.ResultsThe kinetics and thermodynamics of the two homologous chemokines were systematically characterized. Despite their similar tertiary structures, CCL11 and CCL24 show different thermodynamic stability in guanidine hydrochloride titration, with D50% = 2.20 M and 4.96 M, respectively. The kinetics curves clearly show two phases in the folding/unfolding processes of both CCL11 and CCL24, which suggests the existence of an intermediate state in their folding/unfolding processes. The folding pathway of both CCL11 and CCL24 could be well described using a folding model with an on-pathway folding intermediate. However, the folding kinetics and stability of the intermediate state of CCL11 and CCL24 are obviously different.ConclusionOur results suggest homologous proteins with low sequence identity can display almost identical tertiary structure, but very different folding mechanisms, which applies to homologues in the chemokine protein family, extending the general applicability of the above observation.
Highlights
Proteins with low sequence identity but almost identical tertiary structure and function have been valuable to uncover the relationship between sequence, tertiary structure, folding mechanism and functions
Our results show that despite their similar three-dimensional structures and functions, there is an obvious difference in their thermodynamic stability and folding kinetics
By comparing the thermodynamic parameters obtained from kinetics and equilibrium experiments, we find that location of CC chemokine 11 (CCL11) and CC chemokine 24 (CCL24) folding intermediates can be well described using an on-pathway model
Summary
Proteins with low sequence identity but almost identical tertiary structure and function have been valuable to uncover the relationship between sequence, tertiary structure, folding mechanism and functions. Previous work has already shown that a single mutation may greatly affect the structure, stability or function of a protein [3, 4], but some proteins significantly differ in sequence are found to share very similar structures and functions [1, 2] To unravel this mystery, folding of homologous proteins has been compared [5, 6] with peripheral subunit binding domains [7, 8], homologs protein G & L [9], spectrin domain R15, R16 and R17 [1] and RNase family [10]. The disordered N-terminal region [26] together with a
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