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Searching distant homologs of the regulatory ACT domain in phenylalanine hydroxylase

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Abstract

High sequence divergence, evolutionary mobility, and superfold topology characterize the ACT domain. Frequently found in multidomain proteins, these domains induce allosteric effects by binding a regulatory ligand usually to an ACT domain dimer interface. In mammalian phenylalanine hydroxylase (PAH), no contacts are formed between ACT domains, and the domain promotes an allosteric effect despite the apparent lack of ligand binding. The increased functional scenario of this abundant domain encouraged us to search for distant homologs, aiming to enhance the understanding of the ACT domain in general and the ACT domain of PAH in particular. The PDB was searched using the FATCAT server with the ACT domain of PAH as a query. The hits that were confirmed by the SSAP algorithm were divided into known ACT domains (KADs) and potential ACT domains (PADs). The FATCAT/SSAP procedure recognized most of the established KADs, as well 18 so far unrecognized non-redundant PADs with extremely low sequence identities and high divergence in functionality and oligomerization. However, analysis of the structural similarity provides remarkable clustering of the proteins according to similarities in ligand binding. Despite enormous sequence divergence and high functional variability, there is a common regulatory theme among these domains. The results reveal the close relationships of the ACT domain of PAH with amino acid binding and metallobinding ACT domains and with acylphosphatase.

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Abbreviations

AAAH:

Aromatic amino acid hydroxylase

ACYP:

Acylphosphatase

AHAS:

Acetoacetate synthase isozyme III small subuint

AK:

Aspartokinase

ALY:

Transcriptional coactivator

ASR:

Ancestral sequence reconstruction

Atx1:

Metallochaperone

CCS:

Metallochaperone of superoxide dismutase

CE:

Combinatorial extension

CutA1:

Periplasmic divalent cation tolerance protein

Duf190:

Domain unknown function

GCVR:

Glycine cleavage transcriptional repressor

HisG_C:

ATP phophoribosyl transferase

KADs:

Known ACT domains

LPRA:

Leucine-responsive regulatory protein A

MSCS:

Small-conductance mechanosensitive channel

NikR:

Nickel binding regulatory protein

PADs:

Potential ACT domains

PAH:

Phenylalanine hydroxylase

PheA:

Prephenate dehydratase

PII A–B:

P-II-like signaling protein, nitrogen regulatory protein A–B

RMSD:

Root mean square deviation

Rpia:

Ribose-5-phosphate isomerase

SGUF 1–7:

Structural genomics target with unknown function 1–7

SMBD:

Small molecule binding domain

S6 A–B:

30S ribosomal protein S6 A–B

TD:

Threonine deaminase

TH:

Tyrosine hydroxylase

TPH:

Tryptophan hydroxylase

VAO:

Vanillyl-alcohol oxidase

V-ATPase:

Head domain of subunit C

Znta:

Zinc, (lead, cadmium, and mercury) transporting ATPase

3-PGDH:

d-3-Phosphoglycerate dehydrogenase

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Acknowledgments

We are grateful to Prof. Randy Lewis, University of Wyoming, for providing a good research environment for JSL. This research was supported by The Research Council of Norway and Helse-Vest.

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  1. Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009, Bergen, Norway

    Jessica Siltberg-Liberles & Aurora Martinez

  2. Department of Molecular Biology, University of Wyoming, Laramie, WY, 82071, USA

    Jessica Siltberg-Liberles

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  1. Jessica Siltberg-Liberles
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  2. Aurora Martinez
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Correspondence to Aurora Martinez.

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Siltberg-Liberles, J., Martinez, A. Searching distant homologs of the regulatory ACT domain in phenylalanine hydroxylase. Amino Acids 36, 235–249 (2009). https://doi.org/10.1007/s00726-008-0057-2

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