4KDS: Crystal structure of latent rainbow trout plasminogen activator inhibitor 1 (PAI-1)

Very few studies have attributed a direct, active, functional role to N-linked glycans. We describe here an N-linked glycan with a unique role for maintaining the active conformation of a protein of the serpin family. The distinguishing feature of serpins is the "stressed-to-relaxed" transition, in which the reactive center loop inserts as a beta-strand into the central beta-sheet A. This transition forms the basis for the conversion of serpins to the inactive latent state. We demonstrate that plasminogen activator inhibitor-1 (PAI-1) from zebrafish converts to the latent state about 5-fold slower than human PAI-1. In contrast to human PAI-1, fish PAI-1 carries a single N-linked glycan at Asn185 in the gate region through which the reactive center loop passes during latency transition. While the latency transition of human PAI-1 is unaffected by deglycosylation, deglycosylated zebrafish PAI-1 (zfPAI-1) goes latent about 50-fold faster than the glycosylated zfPAI-1 and about 25-fold faster than non-glycosylated human PAI-1. X-ray crystal structure analysis of glycosylated fish PAI-1 confirmed the presence of an N-linked glycan in the gate region and a lack of glycan-induced structural changes. Thus, latency transition of zfPAI-1 is delayed by steric hindrance from the glycan in the gate region. Our findings reveal a previously unknown mechanism for inhibition of protein conformational changes by steric hindrance from N-linked glycans.
PDB ID: 4KDSDownload
MMDB ID: 110361
PDB Deposition Date: 2013/4/25
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 1.6682  Å
Source Organism:
Similar Structures:
Biological Unit for 4KDS: monomeric; determined by author and by software (PISA)
Molecular Components in 4KDS
Label Count Molecule
Protein (1 molecule)
Plasminogen Activator Inhibitor 1
Molecule annotation
Chemical (1 molecule)
* Click molecule labels to explore molecular sequence information.

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