New horizons for lipoprotein receptors: communication by β-propellers

Abstract

sorLA/LR11], the LARGE receptors [low-density lipoprotein receptor-like protein 4, 5, and 6 (LRP4, LRP5, and LRP6)] and the GIANT receptors {low-density lipoprotein receptor-like protein 1, protein 1B, and protein 2 [LRP1, LRP1B, and LRP2 (also known as megalin)]} ( Fig. 1A ). Unrelated to size, the LRs are all modularly constructed from a limited subset of three different domains: the complement type repeat (CR)-domains, the epidermal growth factor (EGF)-like domains, and the ␤ -propellers containing YWTDrepeats (YWTD ␤ -propeller). The related members contain additional structural entities, such as fi bronectin type III (FNIII) domains, vacuolar protein sorting 10 (VPS10) homology domains, and G-domains ( 2, 3 ). Despite this apparent structural simplicity, only few structures have been solved, and the foundation for an explication of their structure-function relations is far from complete.Very early, around the 1980s ( 4 ), it was established that ligand binding to LRs involved the small ( ‫ف‬ 40 residues) CR-domains (also termed receptor class A repeats), which are omnipresent in the family, Fig. 1B . These domains are clustered modularly in disulphide-bonded and Ca 2+ -stabilized regions, and for more than two decades, they have been seen as the sole ligand interaction regions in LRs. In contrast, the ␤ -propellers and the EGF-like domains have merely been seen as spacer regions ensuring a proper distance between clusters of CR-domain binding sites aiding optimized adaptation in ligand binding ( 5 ). In 1998, an analysis of the YWTD-repeat sequences of LRs suggested that each region folds into a ␤ -propeller containing six blades ( 1 ), and in 2001, this was confi rmed by the crystal structure of this region of LDLR ( 6 ). Shortly after, the structure of nidogen-1 followed ( 7 ), showing that Abstract The lipoprotein receptor (LR) family constitutes a large group of structurally closely related receptors with broad ligand-binding specifi city. Traditionally, ligand binding to LRs has been anticipated to involve merely the complement type repeat (CR)-domains omnipresent in the family. Recently, this dogma has transformed with the observation that ␤ -propellers of some LRs actively engage in complex formation too. Based on an in-depth decomposition of current structures and sequences, we suggest that exploitation of the ␤ -propellers as binding targets depends on receptor subgroups. In particular, we highlight the shutter mechanism of ␤ -propellers as a general recognition motif for NxI-containing ligands, and we present indications that the generalized ␤ -propeller-induced ligand release mechanism is not applicable for the larger LRs. For the giant LR members, we present evidence that their ␤ -propellers may also actively engage in ligand binding. We therefore advocate for an increased focus on solving the structure-function relationship of this group of important biological receptors. The family of proteins containing Tyr-Trp-Thr-Asp (YWTD)-repeat ␤ -propellers constitutes a group of structurally related gl...

Structural investigation of the cold-adapted acylaminoacyl peptidase from Sporosarcina psychrophila by atomistic simulations and biophysical methods

“…The C-terminal domain (residue 334-596) has a canonical α/β hydrolase fold with a central eightstranded, mixed β-sheet flanked by α-helices on both sides. A short α-helix (helix α1, residues [5][6][7][8][9][10][11][12][13][14] in the N-terminal region protrudes from the β-propeller domain and connects it to the hydrolase domain.…”

“…This fold is associated with a variety of different biological functions, such as regulation of multi-domain proteins [2], structural stabilization, metal-ion binding [3,4], ligand binding [5] and catalysis [6]. Moreover, several proteins containing β-propeller motifs have been reported to be associated with human diseases, such as cancer, neurodegeneration and arthritis [7].…”

Low pH-induced conformational change and dimerization of sortilin triggers endocytosed ligand release

“…Different families of endocytosis receptors have been identified but our understanding of how their ligands are released at low pH after endocytosis remains incomplete. For the low-density lipoprotein (LDL) endocytosis receptor it has been shown that an intramolecular conformational rearrangement of domains discharges ligands 1 but whether such a conformational change mechanism applies to other endocytosis receptors is not clear 2 .…”

Functional Roles of the Interaction of APP and Lipoprotein Receptors

“…The amino-terminal LBD domain confers ligand specificity, consisting of cysteine-rich complement-type ligand binding-type repeats (LBRs, sometimes called type A repeats). The EGF-precursor domains participate in the pH-dependent release of bound ligands after endocytosis and contain a mixture of EGF receptor-like repeats (EGF-repeats) and YWTD (Tyr-Trp-Thr-Asp) β-propeller repeats (Beglova and Blacklow, 2005 ; Andersen et al, 2013 ; reviewed in Li et al, 2001 ). The intracellular domain is less conserved between the family members, but each of the core members contain at least one NPxY (Asn-Pro-X-Tyr) motif that functions in protein interaction/signal transduction (Trommsdorff et al, 1998 ; Howell et al, 1999 ; Gotthardt et al, 2000 ) and endocytosis (Chen et al, 1990 ).…”