The M2 Module of the Cys-His-rich Domain (CHRD) of PCSK9 Protein Is Needed for the Extracellular Low-density Lipoprotein Receptor (LDLR) Degradation Pathway

Abstract

Background: PCSK9 regulates low-density lipoprotein receptor levels in the liver. The importance of the M1, M2, and M3 modules within the C terminus of PCSK9 is unknown. Results: The M2 module is needed for the extracellular, but not intracellular, activity of PCSK9. Conclusion:The integrity of the M2 module is essential for the extracellular function of PCSK9. Significance: Targeting the M2 module should neutralize circulating PCSK9 and reduce LDL-cholesterol.

An Unbiased Mass Spectrometry Approach Identifies Glypican-3 as an Interactor of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) and Low Density Lipoprotein Receptor (LDLR) in Hepatocellular Carcinoma Cells

“…15). Our study also confirmed that this extracellular binding does not involve PCSK9 CHRD similar to the endogenous inhibitor AnxA2 previously described (19,24). Based on our results, GPC3 interacts with the prodomain and/or catalytic domain of PCSK9 (Fig.…”

“…The expression and secretion of both constructs (ϳ30 -35 kDa) were confirmed by Western blotting (Fig. 5, 1st and 4th lanes), as described previously (19,24). Only hPCSK9⌬CHRD-V5 coimmunoprecipitated with GPC3 by a 4.0-fold enrichment ratio compared with normal IgG (Fig.…”

The Multifaceted Proprotein Convertases: Their Unique, Redundant, Complementary, and Opposite Functions

“…(iv) PCSK9 exhibits a C-terminal Cys-and His-rich domain (CHRD) essential for PCSK9-triggered LDLR degradation (3). Internalization of the PCSK9-LDLR complex in early endosomes (82) does not require the C-terminal CHRD of PCSK9 (83) or its acidic N-terminal 31-59 segment (84), which was shown to bind apoB in LDL (85), and the cytosolic tail of the LDLR is not essential (86). (v) However, targeting of the PCSK9-LDLR complex to lysosomes for degradation does require the integrity of the CHRD (83,87).…”

Pcsk9

“…In support of this model, a recent observation revealed that PCSK9 lacking the M2 domain of the CHRD can still degrade the LDLR intracellularly but not when added outside cells, supporting the presence of 2 distinct sorting and regulatory pathways of the [PCSK9≡LDLR] complex. 51 Interestingly, both the intracellular and the extracellular LDLR degradation activities of PCSK9 require the presence of the CHRD because the [PCSK9-ΔCHRD≡LDLR] complex that lacks this domain, although still capable of internalization into endosomes, does not traffic to lysosomes and is likely recycled to the cell surface. 51,52 This has led to the search of other proteins that may interact with the CHRD and the LDLR and drive the [PCSK9≡LDLR] complex to lysosomes.…”