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Revisiting the context dependence of cofactor‐recruiting motifs

BioEssays2013Vol. 35(7), pp. 585–585

Abstract

Most researchers today will agree that the “one-gene-one-function” concept is out-dated. However, particularly in fields with a long research history, concepts such as “one-gene-one-function” or variations thereof, e.g. “one-motif-one-function”, can be deeply seated and hard to displace. A number of publications in the Hox field have shown that this concept is still alive and present. In contrast, Merabet and Hudry 1 emphasize that, rather than assuming a static combination of “YPWM” motif plus DNA-binding homeodomain as necessary for Hox-proteins functions, Hox and Hox-like proteins should be viewed as a composite of modular sequence-elements. The effective function of a protein will therefore depend on the presence and arrangement of these modules as well as the precise environment the protein is placed in (e.g. availability of cofactors). New lines of evidence support the idea that the precise context into which a protein is placed, can dramatically affect which of its sequence elements will be relevant and which function it will carry out. For example, the YPWM-motif is not the only small linear sequence motif (SLiM) able to interact with the cofactor Extradenticle (Exd). A recent paper on this subject 2 beautifully exemplifies that multiple different motifs capable of interacting with Exd can be present in a single Hox-protein. Depending on the precise context and function examined, different motifs were required for the interaction with Exd. This set of data emphasizes the importance of the context-dependence of SLiMs and indicates a much higher degree of flexibility for how Hox-proteins can exert their function than initially thought. Merabet and Hudry furthermore propose that changing the environment in which a protein acts, thereby changing the availability of its cofactors, allows a protein to adopt new functions. This hypothesis does not exclude the possibility that a direct switch from one SLiM to another is able to change a protein function, but points out that a change in a SLiM is not necessarily required in order for a protein to change its interaction partners or function. Some indication in support of this idea comes from the study of a Hox-related protein called Fushi-tarazu (Ftz). This protein no longer exhibits a Hox-like expression pattern or function in the fruit fly Drosophila and its expression patterns as well as sequence compositions vary considerably across arthropods. Yet, Ftz seems to be present across arthropods, raising the question of how and why Ftz has been retained. Merabet and Hudry noticed similarities in Ftz expression in the arthropods central nervous system (CNS) and suggested that this may be a common function providing the evolutionary constraint for Ftz to be retained. Heffer et al. 3, pursued this question and were able to reaffirm that Ftz expression in the CNS is indeed a unifying feature exhibited by Ftz across arthropods. Fitting the above hypothesis, the presence or absence of two SLiMs (YPWM and LxxLL) in the Ftz protein seemed irrelevant to CNS function and no alternative conserved motif could be identified as correlating with the suggested Ftz function in the CNS. Likewise, none of the “standard” Hox or Ftz interaction partners (Exd or the nuclear receptor Ftz-F1) could be found to co-occur with Ftz in the stages analyzed. An interaction of either Exd or Ftz-F1 with Ftz in this context therefore seems unlikely and it remains to be shown whether other changes in the SLiM composition of Ftz are relevant to its CNS function. Based on the current data, the idea that a change (or loss) of available interaction partners enables a protein to acquire new functions should be kept in mind when analyzing any protein known to interact with other proteins.

Abstract

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