Structure and enzymatic functions of human CD38

Abstract

CD38 is a novel multifunctional protein that serves not only as an antigen but also as an enzyme. It catalyzes the metabolism of cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate, two structurally and functionally distinct Ca(2+) messengers targeting, respectively, the endoplasmic reticulum and lysosomal Ca(2+) stores. The protein has recently been crystallized and its three-dimensional structure solved to a resolution of 1.9 A. The crystal structure of a binary complex reveals critical interactions between residues at the active site and a bound substrate, providing mechanistic insights to its novel multi-functional catalysis. This article reviews the current advances in the understanding of the structural determinants that control the multiple enzymatic reactions catalyzed by CD38.

Figure 1

The multiple enzymatic reactions catalyzed by CD38. Abbreviations used: cyclic ADP-ribose, cADPR; ADP-ribose, ADPR; nicotinic acid adenine dinucleotide phosphate, NAADP; nicotinic acid, NA; ADP-ribose-2’-phosphate, ADPRP.

Figure 2

Crystal Structures of CD38. Left panel. Color codes for the secondary structures are: green, β-structures; red, α-helix; cyan, conserved disulfide bonds; yellow, unique disulfide bond; purple, TLEDTL-conserved motif. Right panel. The van der Waal’s surface of CD38 is shown. The bound substrate molecule at the active site is nicotinamide mononucleotide. The surface of the TLEDTL-conserved motif is colored purple.

Figure 3

A model of native CD38 embedded in a membrane. The surface potential of the extra-membrane domain is based on crystallography, with the negative charged regions colored red, while positively charged are blue. The transparent oval (yellow) indicates the location of the active site pocket. The transmembrane segment is modeled arbitrarily as a helix (gold), while the N-terminal tail as a random coil. Phospholipids of the membrane are colored green.

Figure 4

Stereo views of the active site of CD38. Top panel. A close-up surface view is shown with a molecule of nicotinamide mononucleotide (NMN) bound to the active site pocket. Color coding for its atoms: green, carbon; blue, nitrogen; yellow, phosphorus; red, oxygen. Hydrogen atoms are not shown for clarity. The van der Waal’s surface are colored transparent white, allowing the critical residues to be seen. Color code for atoms of the residues: black, carbon; cyan, nitrogen; red, oxygen; white, hydrogen. Bottom panel. Critical residues and NMN (yellow) are shown. Numbers are distances in Angstroms. Glu146 is colored cyan; Asp155, magenta; Asp147, light gray; and dark gray for Trp125, Trp189, and Gly226.