Abstract
Besides ubiquitin (Ub), humans have a set of ubiquitin-like proteins (UBLs) that can also covalently modify target proteins. To date, less is known about UBLs than Ub and even less is known about the UBL called ubiquitin-fold modifier 1 (UFM1). Currently, our understanding of protein modification by UFM1 (UFMylation) is like a jigsaw puzzle with many missing pieces, and in some cases it is not even clear whether these pieces of data are in the right place. Here we review the current data on UFM1 from structural biology to biochemistry and cell biology. We believe that the physiological significance of protein modification by UFM1 is currently underestimated and there is more to it than meets the eye.
Highlights
Most ubiquitin-like proteins (UBLs) modify target molecules, mainly proteins, and this is required for their physiological functions
This implies that understanding a UBL’s physiological functions requires answers to the following two major questions: (1) what are the mechanisms by which the UBL modifies its targets and how this is regulated and (2) how is this modification translated to a physiological outcome
Using truncations and mutations of UBA5, we showed that the transfer of ubiquitin-fold modifier 1 (UFM1) occurs in a trans-binding mechanism [12]
Summary
Most ubiquitin-like proteins (UBLs) modify target molecules, mainly proteins, and this is required for their physiological functions. .AAccccoorrddininggllyy, ,ththeesseereressididuueessaarree ininththeeininteterrfafacceeooffUUFFMM11ththaattininteterraacctstswwitihthththeeaaddeennyylalattioionnddoommaaininoofftthheeUUFFMM11aaccttiivvaattiinnggeennzzyymmee,, UUBBAA55[1[122].].HHoowweevveerr, ,UUFFMM11s′seelleeccttrroossttaattiiccssuurrffaacceeddiiffffeerrssffrroommUUbb(F(Figiguurree11).).CCoonnsseeqquueennttllyy, ,UUFFMM11 hhaassaappIIooff99.6.6ththaat tisissisgignnifiifciacanntltylyhhigighheerrththaannththaat toof fUUbb(6(6.5.566),),susuggggeestsitninggththaattaat tpphhyysisoiolologgicicaallppHH UUFFMM11, ,ininccoonntrtarasstttotoUUbb, ,isisppoosistiitviveelylychchaargrgeded. UFM1 that binds the UIS of one subunit interacts with the adenylation domain of the other subunit, suggesting a trans-binding mechanism [12]. This differs from the activation of Atg8/10 by Atg that occurs in a cis mechanism [26]. Atg first binds the helical domain of Atg that is located outside the adenylation site, and binds the adenylation domain, which arrives from the same Atg subunit To date, it is not clear why UBA5 functions in a trans-binding mechanism rather than the simpler cis mode of binding. We recently showed that trans-binding stabilizes the dimeric state of UBA5 and that this is needed for the activation of UFM1 [27]
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