Hyaluronan Synthase: The Mechanism of Initiation at the Reducing End and a Pendulum Model for Polysaccharide Translocation to the Cell Exterior

Figure 1

Schematic model of HAS showing the functions needed for HA chain growth at the reducing end and transfer to the cell surface. HAS uses multiple discrete functions (numbers 1–7) to assemble each HA disaccharide (red squares are GlcNAc and green circles are GlcUA). The same HAS protein is indicated in two different situations, at sequential times, as it alternately adds HA-GlcUA-UDP to a new GlcNAc-UDP, using functions 1, 3, and 5 (left), and then adds HA-GlcNAc-UDP to a new GlcUA-UDP, using functions 2, 4, and 6 (right). In this example (variant 1; Table 1) the sugar-UDPs are sequentially added in a continuous alternating manner and each cohort of needed functions cycles between being active (larger black numbers) and inactive (smaller gray numbers) within the active site domains (gray ovals). The functions required to add GlcNAc-UDP to HA-GlcUA-UDP are (left): 1, GlcNAc-UDP acceptor binding; 3, HA-GlcUA-UDP donor binding; 5, HA-GlcUA-UDP: GlcNAc-UDP, β1,3(HA-GlcUA-) transferase; and 7, HA translocation through the membrane. The functions required to add GlcUA-UDP to HA-GlcNAc-UDP are (right): 2, GlcUA-UDP acceptor binding; 4, HA-GlcNAc-UDP donor binding; 6, HA-GlcNAc-UDP: GlcUA-UDP, β1,4(HA-GlcNAc-) transferase; and 7, HA translocation.