Volume 570 Issue 7760, 13 June 2019

Complex relationship

In its active form, the enzyme serine hydroxymethyltransferase 2 (SHMT2) plays an important role in metabolism through its ability to synthesize building blocks that are essential for cell growth and proliferation. The SHMT2 enzyme is activated by its cofactor PLP, the active form of vitamin B6. In its inactive form, SHMT2 is also known to regulate immune signalling through its interaction with the BRISC deubiquitylase complex. In this week’s issue, Elton Zeqiraj, Roger Greenberg and their colleagues present the structure of the human BRISC–SHMT2 complex and reveal an unexpected role for vitamin B6 in controlling complex assembly and function in immune signalling. The structure of the complex was generated at a resolution of 3.8 ångströms using cryo-electron microscopy.BRISC forms a U-shaped structure with a base (black) and two arms (blue). SHMT2 (orange) bridges the two arms and blocks the BRISC active site, inhibiting its enzyme activity until it reaches its specific target. The researchers show that metabolite activation of SHMT2 by PLP (shown as randomly scattered flakes) hampers it from forming a complex with BRISC. The team notes that increased intracellular levels of PLP reduced BRISC–SHMT2 interactions and inflammatory signalling, revealing a direct link between vitamin B6 metabolism and the control of an immune response.

Cover image: Elton Zeqiraj (Univ. Leeds)/Jeroen Claus (Phospho Biomedical Animation)

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