The isolated N-terminal domains of TIMP-1 and TIMP-3 are insufficient for ADAM10 inhibition

Magdalini Rapti , Susan J Atkinson , Meng-Huee Lee , Andrew Trim , Marcia Moss , Gillian Murphy (1)

1 Oncology

ADAM10 is a key member of the ADAM family of disintegrin and metalloproteinases which process membrane associated proteins to soluble forms in a process known as 'shedding'. Among the major targets of ADAM10 are Notch, EphrinA2 and CD44. In many cell based studies of shedding the activity of ADAM10 appears to overlap with that of ADAM17 which has a similar active site topology relative to the other proteolytically active ADAMs. The tissue inhibitors of metalloproteinases, TIMPs, have proved useful in the study of ADAM function since TIMP-1 inhibits ADAM10 but not ADAM17, but both enzymes are inhibited by TIMP-3. In this study we show that, in comparison to ADAM17 and the MMPs, the N-terminal domains of TIMPs alone are insufficient for the inhibition of ADAM10.This knowledge could form the basis for the design of directed inhibitors against different metalloproteinases.

Mots clés: Life Sciences

Magdalini Rapti, Susan J Atkinson, Meng-Huee Lee, Andrew Trim, Marcia Moss, et al.. The isolated N-terminal domains of TIMP-1 and TIMP-3 are insufficient for ADAM10 inhibition. Biochemical Journal, 2008, 411 (2), pp.433-439. ⟨10.1042/BJ20071430⟩. ⟨hal-00478897⟩