Structure-function relationships of epidermal growth factor modules in vitamin K-dependent clotting factors

Abstract

ODULES* homologous to the epidermal growth M factor (EGF) precursor have been found in a large number of proteins with diverse functions.Among these proteins are the vitamin K-dependent clotting factors VII, IX, and X, proteins C and S of the protein C anticoagulant system, and the nonvitamin-K-dependent proteins urokinase (uPA), tissue-type plasminogen activator (tPA), and factor XI1 (Fig l).1.7Progress toward an understanding of structure-function relationships of EGF modules in vitamin K-dependent proteins has advanced along four lines of inquiry.First, the application of high-resolution NMR spectroscopy to structural studies has shown a striking similarity between EGF,"" transforming growth factor-a (TGR-cx),'~"~'~ and the NH,-terminal EGF module of factor X.I3 Second, the properties of factor IX molecules with mutations in the NH,-terminal EGF module have provided insight into the function of these module^.'^.'^Third, EGF module-containing proteolytic fragments of factors IX1* and X 1 9 3 ' 0 and protein Cz1,22 and protein S,U and a recombinant EGF module of factor IX,24 have been shown to bind Ca2+, thus defining a new class of metal ion-binding sites that is presumably crucial to many fundamental biologic p r o c e ~s e s .' ~, ~' ~~~ Fourth, fragments that contain such EGF modules either free or linked to the y-carboxyglutamic acid-containing region are being used to study inter-module interaction^.^^-^'The purpose of this review is to give an account of recent findings regarding the structure and function of EGF modules in vitamin K-dependent plasma proteins and relate the results to advances in the understanding of the function of similar modules in other proteins.For information about the reactions of the vitamin K-dependent enzyme complexes, the reader is referred to a review recently published in this journal.'*There have been several reviews on EGF*8*Z9,30 and EGF modules in nonvitamin K-dependent *The term module is used throughout this report as suggested by Patthy',' and by Baron et al, ' rather than domain, repeat, or motif.However, in accordance with the commonly used nomenclature, vitamin K-dependent proteins lacking the y-carboxyglutamic acidcontaining module will be referred to as, eg, Gla-domainless factor X rather than Gla-moduleless factor X.