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Origin of fibronectin type II (FN2) modules: Structural analyses of distantly-related members of the kringle family idey the kringle domain of neurotrypsin as a potential link between FN2 domains and kringles

¹ Department of Chemistry, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA
² Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, Budapest, Hungary

Reprint requests to: László Patthy, Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, P.O. Box 7, H-1518, Hungary; e-mail: patthy{at}enzim.hu; fax: (361) 4665–465.

Analysis of complete genome sequences has made it clear that fibronectin type II (FN2) modules are present only in the vertebrate lineage, raising intriguing questions about the origin of this module type. Kringle domains display many similarities to FN2 domains; therefore it was suggested previously that they are highly divergent descendants of the same ancestral protein-fold. Since kringles are present in arthropodes, nematodes, and invertebrate chordates as well as in vertebrates, it is suggested that the FN2 domain arose in the vertebrate lineage through major structural modification of the more ancestral kringle fold. To explore this structural transition, in the present work we compare key structural features of two highly divergent kringle domains (the kringle of Caenorhabditis elegans Ror receptor tyrosine kinase and the kringle of rat neurotrypsin) with those of plasminogen kringles and FN2 domains. Our NMR conformation fingerprinting analysis indicates that characteristic ¹H-NMR markers of kringle or FN2 native folding, such as the dispersion of Trp aromatic connectivities and shifts of the Leu⁴⁶/Thr¹⁶ methyl signals, both decrease in the order kringles > neurotrypsin kringle > FN2 domains. These results suggest that the neurotrypsin kringle may represent an intermediate form between typical kringles and FN2 domains.

Keywords: Fibronectin type II domain; kringle domain; neurotrypsin; NMR spectroscopy; evolution of protein folds

Abbreviations: CD, circular dichroism • COSY, two-dimensional NMR chemical shift correlated spectroscopy • CRor, Ror-type receptor tyrosine kinase of C. elegans • CRor/K, the kringle domain of the Ror receptor tyrosine kinase of C. elegans • FN2, fibronectin type II domain • IPTG, isopropyl-ß-D-thiogalactopyranoside • K, kringle domain • NMR, nuclear magnetic resonance • NOESY, two-dimensional NMR nuclear Overhauser effect correlated spectroscopy • NT/K, the kringle domain of neurotrypsin • Pgn/K4, human plasminogen kringle 4 • PDC-109/b, second fibronectin type II domain of bovine PDC-109 • ppm, parts-per-million • PMSF, phenylmethyl sulfonyl fluride • SDS-PAGE, sodium dodecylsulfate polyacrylamide gel electrophoresis

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